Steroid derivatives for the treatment of prostatic hypertrophy their preparation and uses

ABSTRACT

The invention includes compounds of formula (I): ##STR1## in which R 1  is hydrogen, alkyl, aryl-substituted alkyl or aromatic heterocyclic-substituted alkyl; R 2  is aryl-substituted alkyl, aromatic heterocyclic-substituted alkyl or diarylamino; and R 3  is carboxy or a group of formula --CONHSO 2  R 4  wherein R 4  is alkyl; and pharmaceutically acceptable salts and esters of the compounds. The compounds have valuable 5α-reductase inhibitory activity and can thus be used for the treatment and prophylaxis of, inter alia, prostatic hypertrophy as well as other disorders arising from excess levels of 5α-dihydro-testosterone.

This application is a Continuation of application Ser. No. 08/049,140,filed Apr. 19, 1993 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a series of new steroid derivativeswhich have the ability to inhibit the activity or effects oftestosterone 5α-reductase, and can thus be used for the treatment orprophylaxis of prostatic hypertrophy. The invention also providesmethods and compositions using these new compounds, as well as processesfor preparing them.

Testosterone is an active hormone produced in the male by the testes. Itmay be reduced by 5α-reductase to 5α-dihydrotestosterone, which isactive, inter alia, in the prostate.

High levels of 5α-dihydrotestosterone have been implicated in a numberof disorders, including prostatic enlargement, acne, male patternbaldness and female hirsutism. Enlargement of the prostate, otherwiseknown as "prostatic hypertrophy", is an age-related, progressivedisease, which afflicts a high proportion of men over 50 years of age.Since it can result in impaired urinary function, it is generally dealtwith by surgery, which itself has undesired side effects, includingsterility. In an effort to avoid this, attempts have been made todevelop drugs which will prevent or treat the condition. Althoughsuccess has been achieved by the administration of so-called"anti-androgens", such as the oestrogens or derivatives thereof, thesehave resulted in side effects, such as feminisation, which many menpresently consider undesirable.

There is, therefore, a need for a drug capable of treating or preventingprostatic hypertrophy without the feminising effects of theanti-androgens.

The other effects of high levels of 5α-dihydrotestosterone, that isacne, male pattern baldness and female hirsutism, are not medicallyserious, but are very distressing for the sufferers, and no reliabletherapy is currently available.

Since the 5α-reductase inhibitors do not inhibit the activity oftestosterone, it was postulated that they might provide the requiredactivity, and a number of such compounds have been developed whichdemonstrate the accuracy of this hypothesis.

For example, European Patent Publications No. 4949 and 155 096 disclosesome androstane derivatives which are claimed to have 5α-reductaseinhibitory activity. These, however, differ from the compounds of thepresent invention in that they have a heterocyclic ring for theso-called "A-ring" of the steroid moiety, in place of the carbocyclicring of the present compounds.

The closest prior art is believed to be the compounds described inEuropean Patent Publication No. 289 327 and in J. Med. Chem., 33,943-950 (1990), especially at page 945, and in Biochemistry, 29,2815-2824 (1990), all of which disclose the compounds hereinafterreferred to as Compounds A and B, which are17β-(diisopropylcarbamoyl)androsta-3,5-diene-3-carboxylic acid and17β-t-butylcarbamoylandrosta-3,5-diene-3-carboxylic acid, respectively,which have the formulae (A) and (B), respectively: ##STR2## Of these,the t-butyl compound, Compound B, is thought to have the best balance ofactivities, toxicity and usefulness and is currently underinvestigation, and now in Phase III, as a potential commercial drug.

BRIEF SUMMARY OF INVENTION

We have now discovered a series of new androstane derivatives which havevaluable 5α-reductase inhibitory activity, which is substantiallygreater (in our tests by an order of magnitude) than the best of theprior art, namely the t-butyl compound, Compound B.

It is, therefore, an object of the present invention to provide a seriesof new androstane derivatives.

It is a further, and more specific, object of the invention to providesuch compounds having 5α- reductase inhibitory activity.

Other objects and advantages will become apparent as the descriptionproceeds.

Accordingly, the compounds of the present invention are those compoundsof formula (I): ##STR3## wherein: R¹ represents: a hydrogen atom; analkyl group having from 1 to 6 carbon atoms; or a substituted alkylgroup having from 1 to 6 carbon atoms and having at least onesubstituent selected from the group consisting of aryl groups as definedbelow and aromatic heterocyclic groups as defined below;

R² represents:

a substituted alkyl group having from 1 to 6 carbon atoms and having atleast one substituent selected from the group consisting of aryl groupsas defined below and aromatic heterocyclic groups as defined below, andsaid alkyl group further optionally having a single hydroxy or carboxysubstituent; or

a diarylamino group in which the two aryl parts are the same ordifferent and each is as defined below;

R³ represents a carboxy group or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents an alkyl group having from 1 to 6 carbon atoms;

said aryl groups are carbocyclic aromatic groups having from 6 to 14ring carbon atoms and which are unsubstituted or are substituted by atleast one substituent selected from the group consisting of substituentsA, defined below;

said aromatic heterocyclic groups have 5 or 6 ring atoms of which from 1to 3 are hetero-atoms selected from the group consisting of nitrogen,oxygen and sulfur hetero-atoms and the remainder are carbon atoms, saidgroup being unsubstituted or being substituted by at least onesubstituent selected from the group consisting of substituents B,defined below;

said substituents A are selected from the group consisting of: alkylgroups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6carbon atoms; alkoxycarbonyl groups having from 2 to 7 carbon atoms;hydroxy groups; halogen atoms; amino groups; alkylamino groups havingfrom 1 to 6 carbon atoms; dialkylamino groups in which each alkyl parthas from 1 to 6 carbon atoms; aliphatic acylamino groups having from 1to 6 carbon atoms; aromatic acylamino groups in which the aromatic partis a carbocyclic aryl group which has from 6 to 10 ring carbon atoms andwhich is unsubstituted or is substituted by at least one substituentselected from the group consisting of substituents C, defined below;cyano groups; nitro groups; and carboxy groups;

said substituents B are selected from the group consisting of: alkylgroups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6carbon atoms; hydroxy groups; halogen atoms; carbocyclic aryl groupswhich have from 6 to 10 ring carbon atoms and which are unsubstituted orare substituted by at least one substituent selected from the groupconsisting of substituents C, defined below; amino groups; alkylaminogroups having from 1 to 6 carbon atoms; dialkylamino groups in whicheach alkyl part has from 1 to 6 carbon atoms; aliphatic acylamino groupshaving from 1 to 6 carbon atoms; aromatic acylamino groups in which thearomatic part is a carbocyclic aryl group which has from 6 to 10 ringcarbon atoms and which is unsubstituted or is substituted by at leastone substituent selected from the group consisting of substituents C,defined below; nitro groups; and carboxy groups;

said substituents C are selected from the group consisting of: alkylgroups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6carbon atoms; hydroxy groups; halogen atoms; amino groups; alkylaminogroups having from 1 to 6 carbon atoms; dialkylamino groups in whicheach alkyl part has from 1 to 6 carbon atoms; aliphatic acylamino groupshaving from 1 to 6 carbon atoms; cyano groups; nitro groups; and carboxygroups;

and pharmaceutically acceptable salts and esters thereof and otherphysiologically functional derivatives of said compounds of formula (I)which are capable of conversion in the mammalian body to said compoundsof formula (I).

The invention also provides a pharmaceutical composition for thetreatment or prophylaxis of disorders arising from high levels of5α-reductase, notably prostatic hypertrophy, which composition comprisesan effective amount of an active compound in admixture with apharmaceutically acceptable carrier or diluent, wherein said activecompound is selected from the group consisting of compounds of formula(I), defined above, and pharmaceutically acceptable salts and estersthereof.

The invention still further provides a method for the treatment orprophylaxis of disorders arising from high levels of 5α-reductase,notably prostatic hypertrophy, in a mammal, which may be human, whichmethod comprises administering to said mammal an effective amount of anactive compound, wherein said active compound is selected from the groupconsisting of compounds of formula (I), defined above, andpharmaceutically acceptable salts and esters thereof.

The invention also provides processes for the preparation of thecompounds of the present invention, which processes are described inmore detail hereafter.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of the present invention, where R¹ represents an alkylgroup having from 1 to 6 carbon atoms, this may be a straight orbranched chain group having from 1 to 6, preferably from 1 to 4, carbonatoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups, especiallythe methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexylgroups. Of these, we prefer those alkyl groups having from 1 to 4 carbonatoms, more preferably from 1 to 3 carbon atoms, the methyl, ethyl,isopropyl and isobutyl groups being more preferred, and the methyl groupbeing most preferred.

Where R¹ or R² represents a substituted alkyl group, this may be astraight or branched chain group as defined and exemplified above inrelation to the unsubstituted alkyl groups which may be represented byR¹, such as the methyl ethyl propyl isopropyl t-butyl and 1-methylpentylgroups. Particularly preferred alkyl groups which may be represented byR¹ or R² include the alkyl groups having from 1 to 4 carbon atoms, morepreferably alkyl groups having from 1 to 3 carbon atoms, and mostpreferably the methyl, ethyl and isopropyl groups.

In the case of the substituted alkyl groups represented by R¹ or R²,there may be one or more substituents selected from the group consistingof aryl groups and aromatic heterocyclic groups, defined above andexemplified in more detail below. In the case of R² only, there mayoptionally be a further substituent selected from the group consistingof hydroxy groups and carboxy groups. There is no particular limitationon the number of such substituents except such as may be imposed by thenumber of substitutable positions or by steric constraints. In general,however, from 1 to 3 such substituents are preferred, 1 or 2 being morepreferred and 1 being most preferred. Where there are two or moresubstituents, these may be the same as each other or they may bedifferent from each other.

Where the substituent on the substituted alkyl groups represented by R¹or R² is an aryl group, this is a carbocyclic aromatic group (i.e. anaromatic group containing one or more rings, in which all ring atoms arecarbon atoms) having from 6 to 14 ring carbon atoms, preferably from 6to 10 carbon atoms, and more preferably 6 or 10 carbon atoms. Examplesof such groups include the phenyl, indenyl, 1-naphthyl, 2-naphthyl,biphenylenyl, acenaphthylenyl, fluorenyl, phenanthryl and anthrylgroups, of which the phenyl and naphthyl groups are preferred, thephenyl group being most preferred. Such aryl groups may be unsubstitutedor they may be substituted by one or more of substituents A, definedabove and exemplified below. In the case of the substituted groups,there is no particular limitation on the number of such substituents Aexcept such as may be imposed by the number of substitutable positionsor possibly by steric constraints. In general, however, from 1 to 4 suchsubstituents are preferred, from 1 to 3 being more preferred and 1 or 2being most preferred. Where there are two or more substituents, thesemay be the same as each other or they may be different from each other.Examples of such substituents A include:

alkyl groups having from 1 to 6 carbon atoms, such as those exemplifiedabove in relation to the unsubstituted groups which may be representedby R¹ ;

alkoxy groups having from 1 to 6 carbon atoms, such as the methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy,pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1-ethylpropoxy,4-methoxypentyloxy, 3-methoxypentyloxy, 2-methoxypentyloxy,1-methoxypentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 2-ethylbutoxy, hexyloxy and isohexyloxy groups, ofwhich the methoxy and ethoxy groups are preferred;

alkoxycarbonyl groups having from 2 to 7 carbon atoms, that is thealkoxy part has from 1 to 6 carbon atoms, such as the methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl,2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl,4-methoxypentyloxycarbonyl, 3-methoxypentyloxycarbonyl,2-methoxypentyloxycarbonyl, 1-methoxypentyloxycarbonyl,3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl,1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl,1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl,2-ethylbutoxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups,of which the methoxycarbonyl and ethoxycarbonyl groups are preferred;

hydroxy groups;

halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms,of which the fluorine, chlorine and bromine atoms are preferred, thefluorine and chlorine atoms being most preferred;

amino groups;

alkylamino groups having from 1 to 6 carbon atoms, such as themethylamino, ethylamino, propylamino, butylamino, isobutylamino,pentylamino and hexylamino groups; of these, we prefer the groups inwhich the alkyl part has from 1 to 4, more preferably 1 or 2, carbonatoms;

dialkylamino groups in which each alkyl part has from 1 to 6 carbonatoms, such as the dimethylamino, diethylamino, methylethylamino,dipropylamino, diisopropylamino, dibutylamino, dipentylamino,dihexylamino, methylbutylamino and ethylpropylamino groups; of these, weprefer the groups in which each alkyl part has from 1 to 4, morepreferably 1 or 2, carbon atoms;

aliphatic acylamino groups having from 1 to 6 carbon atoms, such as theformylamino, acetylamino, propionylamino, butyrylamino, valerylamino,isovalerylamino, pivaloylamino and hexanoylamino groups, of which thosegroups having from 1 to 5 carbon atoms are preferred, groups having 1 or3 carbon atoms being most preferred;

aromatic acylamino groups in which the aromatic part is a carbocyclicaryl group which has from 6 to 10, preferably 6 or 10, ring carbon atoms(for example the phenyl or naphthyl groups), and which is unsubstitutedor is substituted by at least one substituent selected from the groupconsisting of substituents C, defined above, such as the benzoyl ornaphthoyl groups and substituted derivatives thereof;

cyano groups; nitro groups; and carboxy groups;

Examples of the groups and atoms included in substituents C are the sameas the corresponding groups and atoms included in substituents A andgiven above.

Of these substituents A, we prefer alkyl groups having from 1 to 4carbon atoms, alkoxy groups having from 1 to 4 carbon atoms,alkoxycarbonyl groups having 2 or 3 carbon atoms, hydroxy groups,halogen atoms, amino groups, alkylamino groups having from 1 to 4 carbonatoms, dialkylamino groups in which each alkyl part has from 1 to 4carbon atoms, and aliphatic acylamino groups having from 1 to 3 carbonatoms, more preferably the methyl, ethyl, methoxy, ethoxy,methoxycarbonyl, ethoxycarbonyl, hydroxy, amino, methylamino,ethylamino, dimethylamino, diethylamino, methylethylamino, formylaminoand acetylamino groups, and the fluorine, chlorine and bromine atoms,and most preferably the methyl, methoxy, ethoxy and hydroxy groups, andthe fluorine and chlorine atoms.

Where the substituent on the substituted alkyl groups represented by R¹or R² is an aromatic heterocyclic group, this is a heterocyclic grouphaving 5 or 6 ring atoms in an aromatic ring. The group also has from 1to 3 hetero-atoms selected from the group consisting of nitrogen atoms,oxygen atoms and sulfur atoms, the remaining ring atoms being carbonatoms. In general, where there are three hetero-atoms, we prefer that 1,2 or 3, preferably 2 or 3, are nitrogen atoms and, correspondingly, 2, 1or 0, preferably 1 or 0, are oxygen and/or sulfur atoms. Where there are1 or 2 hetero-atoms, they may be freely selected from nitrogen, oxygenand sulfur atoms. Examples of such groups include the furyl, thienyl,pyridyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups. Of these, weprefer the furyl, thienyl and pyridyl groups, more preferably the furyland thienyl groups, and most preferably the thienyl group. Such aromaticheterocyclic groups may be unsubstituted or they may be substituted byone or more of substituents B, defined above. In the case of thesubstituted groups, there is no particular limitation on the number ofsuch substituents B except such as may be imposed by the number ofsubstitutable positions or possibly by steric constraints. In general,however, from 1 to 3 such substituents are preferred, 1 or 2 being mostpreferred. Where there are two or more substituents, these may be thesame as each other or they may be different from each other. Examples ofsuch substituents B include the corresponding groups and atomsexemplified above in relation to substituents A and aryl groups havingfrom 6 to 10 ring carbon atoms such as those exemplified above andincluded in the aryl groups which may be represented by R¹. Inparticular, preferred substituents include alkyl groups having from 1 to6 carbon atoms (such as those exemplified above in relation to R¹) andhalogen atom (such as the fluorine, chlorine, bromine and iodine atoms).More preferred substituents are alkyl groups having from 1 to 4 carbonatoms, fluorine atoms and chlorine atoms, still more preferably a methylor ethyl group, and most preferably a methyl group.

R³ and possibly substituents A, B or C may represent carboxy groups, andthe group represented by R² may include a carboxy group, and thecompounds of the present invention may therefore form salts and estersas well as other derivatives, which are well known in the art, such asamides. There is no restriction on the nature of such salts, esters andother derivatives, provided that, where they are to be used fortherapeutic purposes, they are pharmaceutically acceptable, that is theyare not less active (or unacceptably less active) or more toxic (orunacceptably more toxic) than the parent compound. However, where thecompounds are to be used for other purposes, for example asintermediates in the preparation of other compounds, even thisrestriction may not apply.

Preferred ester groups are those that can be converted to a carboxygroup in vivo. Examples of such ester groups include:

alkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms,such as those exemplified above in relation to R¹ ;

haloalkyl groups having from 1 to 6, preferably from 1 to 4, carbonatoms, .such as the trifluoromethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-iodoethyl,3-chloropropyl, 4-fluorobutyl and 6-iodohexyl groups, preferably the2,2,2-trichloroethyl and 2-chloroethyl groups;

hydroxyalkyl groups having from 1 to 6, preferably from 1 to 4, carbonatoms, such as the 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl,3,4-dihydroxybutyl and 4-hydroxybutyl groups, preferably the2-hydroxyethyl group;

alkoxyalkyl and alkoxyalkoxyalkyl groups in which the alkyl and alkoxygroups each have from 1 to 6, preferably from 1 to 4, carbon atoms, suchas the methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and2-methoxyethoxymethyl groups, preferably the methoxymethyl group;

the phenacyl group;

alkoxycarbonylalkyl groups in which the alkyl and alkoxy groups eachhave from 1 to 6, preferably from 1 to 4, carbon atoms, such as themethoxycarbonylmethyl group;

cyanoalkyl groups in which the alkyl part has from 1 to 6, preferablyfrom 1 to 4, carbon atoms, such as the cyanomethyl and 2-cyanoethylgroups;

alkylthiomethyl groups in which the alkyl part has from 1 to 6,preferably from 1 to 4, carbon atoms, such as the methylthiomethyl andethylthiomethyl groups;

arylthiomethyl groups in which the aryl part has from 6 to 10 ringcarbon atoms and may be unsubstituted or may be substituted by at leastone substituent selected from the group consisting of substituents C,defined and exemplified above, such as the phenylthiomethyl andnaphthylthiomethyl groups;

alkylsulfonylalkyl groups in which each alkyl part has from 1 to 6,preferably from 1 to 4, carbon atoms, and in which the alkylsulfonylpart may be unsubstituted or may be substituted by at least one halogenatom, such as the 2-methanesulfonylethyl and2-trifluoromethanesulfonylethyl groups;

arylsulfonylalkyl groups in which the aryl part has from 6 to 10 ringcarbon atoms and may be unsubstituted or may be substituted by at leastone substituent selected from the group consisting of substituents C,defined and exemplified above, and the alkyl part has from 1 to 6,preferably from 1 to 4, carbon atoms, such as the 2-benzenesulfonylethyland 2-toluenesulfonylethyl groups;

aralkyl groups in which the aryl part has from 6 to 10 ring carbon atomsand may be unsubstituted or may be substituted by at least onesubstituent selected from the group consisting of substituents C,defined and exemplified above, and the alkyl part has from 1 to 6,preferably from 1 to 3, carbon atoms, such as the benzyl,naphthylmethyl, diphenylmethyl, trityl, 6-phenylhexyl, 4-methylbenzyl,2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl,4-chlorobenzyl and 4-bromobenzyl groups, preferably those aralkyl groupsin which the aryl part is a phenyl group and the alkyl part has from 1to 6, preferably from 1 to 3, carbon atoms, more preferably the benzyl,4-methylbenzyl, 4-chlorobenzyl and 4-bromobenzyl groups;

aryl groups, such as those defined and exemplified above in relation tothe aryl groups which may be substituents on the substituted alkylgroups represented by R¹ and R² ;

silyl groups of formula --SiR^(a) R^(b) R^(c) wherein 1, 2 or 3 ofR^(a), R^(b) and R^(c), which may be the same or different from eachother, each represents an alkyl group having from 1 to 6 carbon atoms(such as those exemplified above in relation to R¹), and correspondingly2, 1 or 0 of R^(a), R^(b) and R^(c) represents an aryl group, such asthose defined and exemplified above in relation to the aryl groups whichmay be substituents on the substituted alkyl groups represented by R¹and R² ; examples of such silyl groups include the trimethylsilyl,triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl,methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl andphenyldiisopropylsilyl groups, preferably the trimethylsilyl,t-butyldimethylsilyl and methyldiphenylsilyl groups;

alkanoyloxyalkyl groups in which the alkanoyl and alkyl groups each havefrom 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms in thecase of alkyl groups or from 1 to 5 carbon atoms in the case of alkanoylgroups, such as the formyloxymethyl, acetoxymethyl, propionyloxymethyl,butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl,isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl,1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl,1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl,1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl,2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl,2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl,1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl,1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl,1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl,1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl,1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl,1-pivaloyloxypentyl and 1-pivaloyloxyhexyl groups, preferably theformyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl,1-propionyloxyethyl, 1-butyryloxyethyl and 1-pivaloyloxyethyl groups,more preferably the acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl,1-butyryloxyethyl and 1-pivaloyloxyethyl groups, most preferably thepivaloyloxymethyl and 1-pivaloyloxyethyl groups;

cycloalkanecarbonyloxyalkyl groups in which the cycloalkane part hasfrom 5 to 7, preferably 5 or 6, carbon atoms and the alkyl part has from1 to 6, preferably from 1 to 4, carbon atoms (such as those exemplifiedabove in relation to R¹), such as the cyclopentanecarbonyloxymethyl,cyclohexanecarbonyloxymethyl, 1-(cyclopentanecarbonyloxy)ethyl,1-(cyclohexanecarbonyloxy) ethyl, 1-(cyclopentanecarbonyloxy)propyl,1-(cyclohexanecarbonyloxy)propyl, 1-(cyclopentanecarbonyloxy)butyl,1-(cyclohexanecarbonyloxy)butyl, cycloheptanecarbonyloxymethyl,1-(cycloheptanecarbonyloxy)ethyl, 1-(cycloheptanecarbonyloxy)propyl and1-(cycloheptanecarbonyloxy)butyl groups, preferably thecyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl,1-(cyclopentanecarbonyloxy) ethyl and 1-(cyclohexanecarbonyloxy) ethylgroups;

alkoxycarbonyloxyalkyl groups in which the alkyl and alkoxy groups eachhave from 1 to 6, preferably from 1 to 4, carbon atoms, such as themethoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl,butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl,pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl,1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl,1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl,1-butoxycarbonyloxyethyt, 1-isobutoxycarbonyloxyethyl,1-pentyloxycarbonyloxyethyl, 1-hexyloxycarbonyloxyethyl,2-methoxycarbonyloxyethyl, 2-ethoxycarbonyloxyethyl,2-propoxycarbonyloxyethyl, 2-isopropoxycarbonyloxyethyl,2-butoxycarbonyloxyethyl, 2-isobutoxycarbonyloxyethyl,2-pentyloxycarbonyloxyethyl, 2-hexyloxycarbonyloxyethyl,1-methoxycarbonyloxypropyl, 1-ethoxycarbonyloxypropyl,1-propoxycarbonyloxypropyl, 1-isopropoxycarbonyloxypropyl,1-butoxycarbonyloxypropyl, 1-isobutoxycarbonyloxypropyl,1-pentyloxycarbonyloxypropyl, 1-hexyloxycarbonyloxypropyl,1-methoxycarbonyloxybutyl, 1-ethoxycarbonyloxybutyl,1-propoxycarbonyloxybutyl, 1-isopropoxycarbonyloxybutyl,1-butoxycarbonyloxybutyl, 1-isobutoxycarbonyloxybutyl,1-methoxycarbonyloxypentyl, 1-ethoxycarbonyloxypentyl,1-methoxycarbonyloxyhexyl and 1-ethoxycarbonyloxyhexyl groups,preferably the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl,butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl,1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl,1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl,1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl,1-methoxycarbonyloxypropyl, 1-ethoxycarbonyloxypropyl,1-propoxycarbonyloxypropyl, 1-isopropoxycarbonyloxypropyl,1-butoxycarbonyloxypropyl, 1-isobutoxycarbonyloxypropyl,1-methoxycarbonyloxybutyl, 1-ethoxycarbonyloxybutyl,1-propoxycarbonyloxybutyl, 1-isopropoxycarbonyloxybutyl,1-butoxycarbonyloxybutyl and 1-isobutoxycarbonyloxybutyl groups, morepreferably the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl,butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl,1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl,1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl,1-butoxycarbonyloxyethyl and 1-isobutoxycarbonyloxyethyl groups, andmost preferably the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl groups;

cycloalkyloxycarbonyloxyalkyl groups in which the cycloalkyl part hasfrom 5 to 7, preferably 5 or 6, carbon atoms and the alkyl part has from1 to 6, preferably from 1 to 4, carbon atoms (such as those exemplifiedabove in relation to R¹), such as the cyclopentyloxycarbonyloxymethyl,cyclohexyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl,1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl,1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl,1-(cyclohexyloxycarbonyloxy)butyl, cycloheptyloxycarbonyloxymethyl,1-(cycloheptyloxycarbonyloxy)ethyl, 1-(cycloheptyloxycarbonyloxy)propyland 1-(cycloheptyloxycarbonyloxy)butyl groups, preferably thecyclopentyloxycarbonylooxymethyl, cyclohexyloxycarbonyloxymethyl,1-(cyclopentyloxycarbonyloxy)ethyl and 1-(cyclohexyloxycarbonyloxy)ethylgroups;

(5-aryl- or 5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl groups in which thearyl part has from 6 to 10 ring carbon atoms and may be unsubstituted ormay be substituted by at least one substituent selected from the groupconsisting of substituents C, defined and exemplified above, and thealkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms (suchas those exemplified above in relation to R¹), such as the(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-fluorophenyl)- 2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl groups, preferably the(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl groups, and most preferably the(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; and

the phthalidyl group.

Of these, we especially prefer: alkyl groups having from 1 to 4 carbonatoms; benzyl groups; substituted benzyl groups having from 1 to 3substituents selected from the group consisting of methyl, ethyl,methoxy and ethoxy groups and fluorine and chlorine atoms; thediphenylmethyl group; the naphthylmethyl groups; alkanoyloxyalkyl groupsin which the alkanoyl part has from 1 to 5 carbon atoms and the alkylpart has from 1 to 4 carbon atoms; cycloalkanecarbonyloxyalkyl groups inwhich the cycloalkyl part has from 5 to 7 ring carbon atoms and thealkyl part has from 1 to 4 carbon atoms; alkoxycarbonyloxyalkyl groupsin which the alkoxy and alkyl parts each have from 1 to 4 carbon atoms;cycloalkyloxycarbonyloxyalkyl groups in which the cycloalkyl part hasfrom 5 to 7 ring carbon atoms and the alkyl part has from 1 to 4 carbonatoms; (5-phenyl- or 5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl groups inwhich the alkyl part has from 1 to 4 carbon atoms; and the phthalidylgroup.

More preferred ester groups include: alkyl groups having from 1 to 4carbon atoms; benzyl groups; alkanoyloxyalkyl groups in which thealkanoyl part has from 1 to 5 carbon atoms and the alkyl part has I or 2carbon atoms; cycloalkanecarbonyloxyalkyl groups in which the cycloalkylpart has from 5 to 7 ring carbon atoms and the alkyl part has 1 or 2carbon atoms; alkoxycarbonyloxyalkyl groups in which the alkoxy part hasfrom 1 to 4 carbon atoms and the alkyl part has 1 or carbon atoms;cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl part has from5 to 7 ring carbon atoms and the alkyl part has 1 or 2 carbon atoms;[5-phenyl-, 5-methyl- or 5-ethyl- 2-oxo-1,3-dioxolen-4-yl)methyl groups;and the phthalidyl group.

The most preferred ester groups include: methyl groups, ethyl groups,pivaloyloxymethyl groups, ethoxycarbonyloxymethyl groups,1-(ethoxycarbonyloxy)ethyl groups, isopropoxycarbonyloxymethyl groups,1-(isopropoxycarbonyloxy)ethyl groups,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group and phthalidyl groups.

Those compounds of the present invention which contain a carboxy groupcan also form salts. Examples of such salts include: salts with analkali metal, such as sodium, potassium or lithium; salts with analkaline earth metal, such as barium or calcium; salts with anothermetal, such as magnesium or aluminum; ammonium salts; organic basesalts, such as a salt with triethylamine, diisopropylamine,cyclohexylamine, dicyclohexylamine and guanidine; and salts with a basicamino acid, such as lysine or arginine. Also, where the compound of thepresent invention contains a basic group, such as an amino group, in itsmolecule, it can form acid addition salts. Examples of such acidaddition salts include: salts with mineral acids, especially hydrohalicacids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid orhydrochloric acid), nitric acid, carbonic acid, sulfuric acid orphosphoric acid; salts with lower alkylsulfonic acids, such asmethanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonicacid; salts with arylsulfonic acids, such as benzenesulfonic acid orp-toluenesulfonic acid; salts with organic carboxylic acids, such asacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid,malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid,lactic acid, gluconic acid or citric acid; and salts with amino acids,such as glutamic acid or aspartic acid.

Examples of alkyl groups which may be represented by R⁴ include thealkyl groups exemplified above in relation to R¹, especially the methyland ethyl groups.

In general, in the compounds of the present invention, we prefer that R¹represents a hydrogen atom and R² is as defined above.

Preferred groups of formula --NR¹ R² include: the benzylamino, (2-, 3-or 4-methylbenzyl)amino, (2-, 3- or 4-methoxybenzyl)amino, (2-, 3- or4-fluorobenzyl)amino, (2-, 3- or 4-chlorobenzyl)amino, phenethylamino,(2-, 3- or 4-methylphenethyl)amino, (2-, 3- or 4-methoxyphenethyl)amino,(2-, 3- or 4-fluorophenethyl)amino, (2-, 3- or 4-chlorophenethyl)amino,(3-phenylpropyl)amino, (1-methyl-1-phenylethyl)amino, [1-methyl-1- (2-,3- or 4-methylphenyl) ethyl]amino, [1-methyl-1-(2-, 3- or4-methoxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-fluorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-chlorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-hydroxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or 4-aminophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or 4-methylaminophenyl)ethyl]amino,[1-methyl-1- (2-, 3- or 4-ethylaminophenyl)ethyl]amino, [1-methyl-1-(2-,3- or 4-dimethylaminophenyl)ethyl]amino, [1-methyl-1- (2-, 3- or4-acetamidophenyl)ethyl]amino, [1-methyl-1-(2,3-, 2,4-, 2,5-, 2,6-,3,4-, 3,5- or 3,6-dimethoxyphenyl)ethyl] amino,(1,1-dimethyl-2-phenylethyl)amino, [1,1-dimethyl-2-(2-, 3- or4-methylphenyl)ethyl]amino, [1,1-dimethyl-2-(2-, 3- or4-methoxyphenyl)ethyl]amino, [1,1-dimethyl-2-(2-, 3- or 4-fluorophenyl)ethyl]amino, [1,1-dimethyl-2-(2-, 3- or4-chlorophenyl)ethyl]amino, benzhydrylamino, [(2-, 3- or 4-), (2'-, 3'-or 4'-)-dimethylbenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dimethoxybenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-difluorobenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dihydroxybenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-diaminobenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-di(dimethylamino)benzhydryl]amino, (2-, 3- or4-methylbenzhydryl)amino, (2-, 3- or 4-methoxybenzhydryl)amino, (2-, 3-or 4-fluorobenzhydryl)amino, (2-, 3- or 4-chlorobenzhydryl)amino, (2-,3- or 4-hydroxybenzhydryl)amino, (2-, 3- or 4-aminobenzhydryl)amino,(2-, 3- or 4-dimethylaminobenzhydryl)amino, (1,1-diphenylethyl)amino,(1,2-diphenylethyl)amino, [2-(2-, 3- or4-methylphenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-methoxyphenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-fluorophenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-chlorophenyl)-1-phenylethyl]amino, [1- (2-, 3- or4-fluorophenyl)-2-(2-, 3- or 4-fluorophenyl)ethyl]amino, [1- (2-, 3- or4-chlorophenyl)-2-(2-, 3- or 4-chlorophenyl)ethyl]amino, [1-(2-, 3- or4-chlorophenyl)-2-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [1-(2-, 3- or4-methylphenyl)-2-(2-, 3- or 4-methylphenyl) ethyl]amino, [1-(2-, 3- or4-hydroxyphenyl)-2-(2-, 3- or 4-hydroxyphenyl)ethyl]amino, [1-(2-, 3- or4- aminophenyl)-2-(2-, 3- or 4-aminophenyl)ethyl]amino, [1-(2-, 3- or4-dimethylaminophenyl)-2-(2-, 3- or 4-dimethylaminophenyl)ethyl]amino,[2-(2-, 3- or 4-fluorophenyl)-1-(2-, 3- or 4-methylphenyl)ethyl]amino,[2-(2-, 3- or 4-fluorophenyl)-1-(2-, 3- or 4-methoxyphenyl)ethyl]amino,[2-(2-, 3 - or 4-hydroxyphenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-aminophenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-dimethylaminophenyl)-1-phenylethyl]amino, [1-(2-, 3- or4-methoxyphenyl)-2-phenylethyl]amino, (1-methyl-1,2-diphenylethyl)amino,(2,2-diphenylethyl)amino, [2-(2-, 3- or 4-methylphenyl)-2-(2-, 3- or4-methylphenyl)ethyl]amino, [2-(2-, 3- or 4-methoxyphenyl)-2-(2-, 3- or4-methoxyphenyl) ethyl]amino, (1-benzyl-4-phenylbutyl)amino,(1,1-diphenylethyl)amino, [1-(2-, 3- or 4-fluorophenyl)-1-(2-, 3- or4-fluorophenyl)ethyl]amino, [1-(2-, 3- or 4-methylphenyl)-1-(2-, 3- or4-methylphenyl)ethyl]amino, [1-(2-, 3- or 4-methoxyphenyl)-1-(2-, 3- or4-methoxyphenyl)ethyl]amino, [1-(2-, 3- or4-hydroxyphenyl)-1-phenylethyl]amino, [1-(2-, 3- or4-aminophenyl)-1-phenylethyl]amino, [1-(2-, 3- or4-dimethylaminophenyl)-1-phenylethyl]amino, tritylamino, [(2-, 3- or4-), (2'-, 3'- or 4'-), (2"-, 3"- or 4"-)trimethyltrityl]amino [(2-, 3-or 4-) (2'-, 3'- or 4'-), (2"-, 3"- or 4"-)trifluorotrityl]amino,(1-benzyl-2-phenylethyl)amino, [1-(2-, 3- or 4-fluorobenzyl)-2-(2-, 3-or 4-fluorophenyl)ethyl]amino, (1-benzyl-1-methyl-2-phenylethyl)amino,[1-(2-, 3- or 4-chlorobenzyl)-2-(2-, 3- or 4-chlorophenyl)ethyl]amino,[1-(2-, 3- or 4-fluorobenzyl)-2-(2-, 3- or4-fluorophenyl)-1-methylethyl]amino, [1-methyl-2-(2-, 3- or4-methylphenyl)-3-(2-, 3- or 4-methylphenyl)propyl]amino, [2-(2-, 3- or4-fluoroyphenyl)-3-(2-, 3- or 4-fluoroyphenyl)-1-methylpropyl]amino,(1,3-diphenylpropyl)amino, [1-(2-, 3- or 4-methylphenyl)-3-(2-, 3- or4-methylphenyl)propyl]amino, [1-(2-, 3- or 4-methoxyphenyl)-3-(2-, 3- or4-methoxyphenyl)propyl]amino, (1,4-diphenylbutyl)amino, [1-(2-, 3- or4-chlorophenyl)-4-(2-, 3- or 4-chlorophenyl)butyl]amino, [1-(2-, 3- or4-methoxyphenyl)-4-(2-, 3- or 4-methoxyphenyl)butyl]amino,(1-methyl-3,3-diphenylpropyl)amino, [3-(2-, 3- or 4-fluorophenyl)-3-(2-,3- or 4-fluorophenyl)-1-methylpropyl]amino, [1-methyl-3-(2-, 3- or4-methylphenyl)-3-(2-, 3- or 4-methylphenyl)propyl]amino,N-benzyl-N-methylamino, N-benzyl-N-ethylamino,N-benzyl-N-isopropylamino, N-benzyl-N-isobutylamino,N-benzyl-N-t-butylamino, N-(2-, 3- or 4-fluorobenzyl)-N-isopropylamino,N-(2-, 3- or 4-chlorobenzyl)-N-isopropylamino, N-(2-, 3- or4-methylbenzyl)-N-isopropylamino, N-(2-, 3- or4-methoxybenzyl)-N-isopropylamino, N-(2-, 3- or4-hydroxybenzyl)-N-isopropylamino, N,N-dibenzylamino, N-benzyl-N-(2-, 3-or 4-methoxybenzyl)amino, N-(2-, 3- or 4-fluorobenzyl)-N-(2-, 3- or4-fluorobenzyl)amino, N-(2-, 3- or 4-methylbenzyl)-N-(2-, 3- or4-methylbenzyl)amino, N-(2-, 3- or 4-methoxybenzyl)-N-(2-, 3- or4-methoxybenzyl)amino, N-(2-, 3- or 4-hydroxybenzyl)-N-(2-, 3- or4-hydroxybenzyl)amino, N-(2-, 3- or 4-aminobenzyl)-N-(2-, 3- or4-aminobenzyl)amino, N-(2-, 3- or 4-dimethylaminobenzyl)-N-(2-, 3- or4-dimethylaminobenzyl)amino, N-benzyl-N-phenylethylamino,N-benzyl-N-(1-phenylethyl)amino,N-benzyl-N-(1-methyl-1-phenylethyl)amino, N,N-diphenylethylamino,N,N-bis(1-phenylethyl)amino, N-benzyl-N-(3-phenylpropyl)amino, (2- or 3-furylmethyl)amino, (2- or 3-thienylmethyl)amino, (2-, 3- or4-pyridylmethyl)amino, (2- or 5-methyl-2- or 3-furylmethyl)amino, (2- or5-methyl-2- or 3-thienylmethyl)amino, [2-(2- or 3-furyl)ethyl]amino,[2-(2- or 3-thienyl)ethyl]amino, [3-(2- or 3- furyl)propyl]amino, [3-(2-or 3-thienyl)propyl]amino, [bis(2- or 3-furyl)methyl]amino, [bis(2- or3-thienyl)methyl]amino, [1,1-bis(2- or 3-furyl)ethyl]amino, [1,1-bis(2-or 3-thienyl)ethyl]amino, [(2- or 5-methyl-2- or 3-furylmethyl), (2- or5-methyl-2- or 3-furylmethyl]amino, [(2- or 5-methyl-2- or3-thienylmethyl), (2- or 5-methyl-2- or 3-thienylmethyl]amino, [1-(2- or3- furyl)-1-methylethyl]amino, [ 1-(2- or3-thienyl)-1-methylethyl]amino, [1-(2- or 5-methyl-2- or3-thienyl)-1-methylethyl]amino, [1-(2- or 3-furyl)-2-(2- or3-furyl)ethyl]amino, [1-(2- or 5-methyl-2- or3-furyl)-1-methylethyl]amino, [1-(2- or 3-thienyl)-2-(2- or3-thienyl)ethyl]amino, [1-(2- or 3-furyl)-2-phenylethyl]amino, [1-(2- or3-furyl)-2-(2-, 3- or 4-methylphenyl)ethyl]amino, [2-phenyl-1-(2- or3-thienyl)ethyl]amino, [1-phenyl-2-(2- or 3-thienyl)ethyl]amino, [2-(2-,3- or 4-methylphenyl)-1-(2- or 3-thienyl)ethyl]amino, [2-(2-, 3- or4-chlorophenyl)-1-(2- or 3-thienyl)ethyl]amino, [2-(2-, 3- or4-fluorophenyl)-1-(2- or 3-thienyl)ethyl]amino, [2-(2-, 3- or4-methoxyphenyl)-1-(2- or 3-thienyl)ethyl]amino, N-(2- or3-furylmethyl)-N-(2- or 3-furylmethyl)amino, N-(2- or3-thienylmethyl)-N-(2- or 3-thienylmethyl)amino, [1-(2-, 3- or4-fluorophenyl)-2-(2- or 3-thienyl)ethyl]amino, N-benzyl-N-(2- or3-furylmethyl)amino, N-benzyl-N-(2- or 3-thienylmethyl)amino,(2-hydroxy-1,2-diphenylethyl)amino, N',N'-diphenylhydrazino, N'-(2-, 3-or 4-methylphenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-methoxyphenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-chlorophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-fluorophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-hydroxyphenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-aminophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-dimethylaminophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-acetamidophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-methylphenyl)-N'-(2-, 3- or 4-methylphenyl)hydrazino and N'-(2-, 3- or4-methoxyphenyl)-N'-(2-, 3- or 4-methoxyphenyl)hydrazino groups.

More preferred groups of formula --NR¹ R² include: the(1-methyl-1-phenylethyl)amino, [1-methyl-1-(2-, 3- or4-methylphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-methoxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-fluorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-chlorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-hydroxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-aminophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-dimethylaminophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-acetamidophenyl)ethyl]amino, [1-methyl-1-(2,3-, 2,4-, 2,5-, 2,6-,3,4-, 3,5- or 3,6-dimethoxyphenyl)ethyl]amino,(1,1-dimethyl-2-phenylethyl)amino, benzhydrylamino, [(2-, 3- or 4-),(2'-, 3'- or 4'-)-dimethylbenzhydryl]amino, [(2-, 3- or 4-) , (2'-, 3'-or 4'-)-dimethoxybenzhydryl]amino, [(2-, 3- or 4-) , (2'-, 3'- or4'-)-difluorobenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dihydroxybenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-diaminobenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-di(dimethylamino)benzhydryl]amino, (2-, 3- or4-methylbenzhydryl)amino, (2-, 3- or 4-methoxybenzhydryl)amino, (2-, 3-or 4- fluorobenzhydryl)amino, (2-, 3- or 4-chlorobenzhydryl)amino, (2-,3- or 4-hydroxybenzhydryl)amino, (2-, 3- or 4- aminobenzhydryl)amino,(2-, 3- or 4-dimethylaminobenzhydryl)amino, (1,1-diphenylethyl)amino,(1,2-diphenylethyl)amino, [2-(2-, 3- or4-chlorophenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-fluorophenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-methylphenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-methoxyphenyl)-1-phenylethyl]amino, [1-(2-, 3- or4-fluorophenyl)-2-(2-, 3- or 4-fluorophenyl)ethyl]amino, [1-(2-, 3- or4-chlorophenyl)-2-(2-, 3- or 4-chlorophenyl)ethyl]amino, [1-(2-, 3- or4- chlorophenyl)-2-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [1-(2-, 3- or4-methylphenyl)-2-(2-, 3- or 4-methylphenyl)ethyl]amino, [1-(2-, 3- or4-hydroxyphenyl)-2-(2-, 3- or 4-hydroxyphenyl)ethyl]amino, [1-(2-, 3- or4-aminophenyl)-2-(2-, 3- or 4-aminophenyl)ethyl]amino, [1-(2-, 3- or4-dimethylaminophenyl)-2-(2-, 3- or 4-dimethylaminophenyl)ethyl]amino,[2-(2-, 3- or 4-fluorophenyl)-1-(2-, 3- or 4-methylphenyl)ethyl]amino,[2-(2-, 3- or 4-fluorophenyl)-1-(2-, 3- or 4-methoxyphenyl)ethyl]amino,[2-(2-, 3- or 4-hydroxyphenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-aminophenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-dimethylaminophenyl)-1-phenylethyl]amino, [1-(2-, 3- or4-methoxyphenyl)-2-phenylethyl]amino, (1-methyl-1,2-diphenylethyl)amino,(2,2-diphenylethyl)amino, (1,1-diphenylethyl)amino, [1-(2-, 3- or4-fluorophenyl)-1-(2-, 3- or 4-fluorophenyl)ethyl]amino, [1-(2-, 3- or4-methylphenyl)-1-(2-, 3- or 4-methylphenyl)ethyl]amino, [1-(2-, 3- or4-methoxyphenyl)-1-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [1-(2-, 3- or4- hydroxyphenyl)-1-phenylethyl]amino, [1-(2-, 3- or4-aminophenyl)-1-phenylethyl]amino, [1-(2-, 3- or4-dimethylaminophenyl)-1-phenylethyl]amino, tritylamino,(1-benzyl-2-phenylethyl)amino, (1-benzyl-1-methyl-2-phenylethyl)amino,N-benzyl-N-methylamino, N-benzyl-N-ethylamino,N-benzyl-N-isopropylamino, N-benzyl-N-isobutylamino,N-benzyl-N-t-butylamino, N-(2-, 3- or 4-fluorobenzyl)-N-isopropylamino,N-(2-, 3- or 4-chlorobenzyl)-N-isopropylamino, N-(2-, 3- or4-methylbenzyl)-N-isopropylamino, N-(2-, 3- or4-methoxybenzyl)-N-isopropylamino, N-(2-, 3- or4-hydroxybenzyl)-N-isopropylamino, N,N-dibenzylamino, N-benzyl-N-(2-, 3-or 4-methoxybenzyl)amino, N-(2-, 3- or 4-fluorobenzyl)-N-(2-, 3- or4-fluorobenzyl)amino, N-(2 -, 3- or 4-methylbenzyl)-N-(2-, 3- or4-methylbenzyl)amino, N-(2-, 3- or 4-methoxybenzyl)-N-(2-, 3- or4-methoxybenzyl)amino, N-(2-, 3- or 4-hydroxybenzyl)-N-(2-, 3- or4-hydroxybenzyl)amino, N-(2-, 3- or 4-aminobenzyl)-N-(2-, 3- or4-aminobenzyl)amino, N-(2-, 3- or 4-dimethylaminobenzyl)-N-(2-, 3- or4-dimethylaminobenzyl)amino, [bis(2- or 3-furyl)methyl]amino, [bis(2- or3-thienyl)methyl]amino, [1,1-bis(2- or 3-thienyl)ethyl]amino, [(2- or5-methyl-2- or 3-thienyl), (2- or 5-methyl-2- or 3-thienyl)methyl]amino,[1-(2- or 3-thienyl)-1-methylethyl]amino, [1-(2- or 5-methyl-2- or3-thienyl)-1-methylethyl]amino, [1-(2- or 3-furyl)-1-methylethyl]amino,[1-(2 - or 5-methyl-2- or 3-furyl)-1-methylethyl]amino, [1-(2- or3-furyl)-2-(2- or 3- furyl)ethyl]amino, [1-(2- or3-furyl)-1-methylethyl]amino, [1-(2- or 3-thienyl)-2-(2- or3-thienyl)ethyl]amino, [1-(2- or 3-furyl)-2-phenylethyl]amino,[2-phenyl-1-(2- or 3-thienyl)ethyl]amino, [1-phenyl-2-(2- or3-thienyl)ethyl]amino, [2-(2-, 3- or 4-methylphenyl)-1-(2- or3-thienyl)ethyl]amino, [2-(2-, 3- or 4-chlorophenyl)-1 -(2- or3-thienyl)ethyl]amino, [2-(2-, 3- or 4-fluorophenyl)-1-(2- or3-thienyl)ethyl]amino, [2-(2-, 3- or 4-methoxyphenyl)-1-(2- or3-thienyl)ethyl]amino, N-(2- or 3-thienylmethyl)-N-(2- or3-thienylmethyl)amino, [1-(2-, 3- or 4-fluorophenyl)-2-(2- or3-thienyl)ethyl]amino, N',N'-diphenylhydrazino, N'-(2-, 3- or4-methylphenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-methoxyphenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-chlorophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-fluorophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-hydroxyphenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-aminophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-dimethylaminophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-acetamidophenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-methylphenyl)-N'-(2 -, 3- or 4-methylphenyl)hydrazino and N'-(2-, 3-or 4-methoxyphenyl)-N'-(2-, 3- or 4-methoxyphenyl)hydrazino groups.

Still more preferred groups of formula --NR¹ R² include: the(1-methyl-1-phenylethyl)amino, [1-methyl-1-(2-, 3- or4-methylphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-methoxyphenyl)ethyl]amino, [1-methyl-1-(3,4- or3,5-dimethoxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-fluorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-chlorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-hydroxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-dimethylaminophenyl)ethyl]amino, (1,1-dimethyl-2-phenylethyl)amino,benzhydrylamino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dimethylbenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dimethoxybenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-difluorobenzhydryl]amino [(2-, 3- or 4-), (2'-, 3'- or4'-)-dichlorobenzhydryl]amino, (2-, 3- or 4-methylbenzhydryl)amino, (2-,3- or 4-methoxybenzhydryl)amino, (2-, 3- or 4-fluorobenzhydryl)amino,(2-, 3- or 4-chlorobenzhydryl)amino, (2-, 3- or4-hydroxybenzhydryl)amino, (2-, 3- or 4-dimethylaminobenzhydryl)amino,(1,1-diphenylethyl)amino, (1,2-diphenylethyl)amino, [2-(2-, 3- or4-chlorophenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-fluorophenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-methylphenyl)-1-phenylethyl]amino, [2-(2-, 3- or4-methoxyphenyl)-1-phenylethyl]amino, N,N-dibenzylamino, N-(2-, 3- or4-fluorobenzyl)-N-(2-, 3- or 4-fluorobenzyl)amino, N-(2-, 3- or4-methylbenzyl)-N-(2-, 3- or 4-methylbenzyl)amino, N-(2-, 3- or4-methoxybenzyl)-N-(2-, 3- or 4-methoxybenzyl)amino, [1-(2- or3-thienyl)-1-(2- or 3-thienyl)methyl]amino, [2-phenyl-1-(2- or3-thienyl)ethyl]amino, [1-methyl-1-(2- or 3-thienyl)ethyl]amino,[1-methyl-1-(2- or 5-methyl-2- or 3-thienyl)ethyl]amino, [1-methyl-1-(2-or 3-furylethyl]amino, [1-methyl-1-(2- or 5-methyl-2-furyl)ethyl]amino,N',N'-diphenylhydrazino, N'-(2-, 3- or4-methoxyphenyl)-N'-phenylhydrazino, N'-(2-, 3- or4-fluorophenyl)-N'-phenylhydrazino and N'-(2-, 3- or4-methoxyphenyl)-N'-(2-, 3- or 4-methoxyphenyl)hydrazino.

The most preferred groups of formula --NR¹ R² include: the(1-methyl-1-phenylethyl)amino, [1-methyl-1-(2-, 3- or4-methylphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-methoxyphenyl)ethyl]amino, [1-methyl-1-(3,4- or3,5-dimethoxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-fluorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-chlorophenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-hydroxyphenyl)ethyl]amino, [1-methyl-1-(2-, 3- or4-dimethylaminophenyl)ethyl]amino, (1,1-dimethyl-2-phenylethyl)amino,benzhydrylamino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dimethylbenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dimethoxybenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-difluorobenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or4'-)-dichlorobenzhydryl]amino, (2-, 3- or 4-methylbenzhydryl)amino, (2-,3- or 4-methoxybenzhydryl)amino, (2-, 3- or 4-hydroxybenzhydryl)amino,(1,1-diphenylethyl)amino, [1-methyl-1-(2- or 3-thienyl)ethyl]amino,[1-methyl-1-(2- or 5-methyl-2- or 3-thienyl)ethyl]amino, [1-methyl-1-(2-or 3-furylethyl]amino and [1-methyl-1-(2- or 5-methyl-2- or 3-furyl)ethyl]amino groups.

The compounds of the present invention may, depending upon the nature ofthe substituent groups, contain one or more asymmetric carbon atoms intheir molecules, and in this case can form optical isomers. Althoughthese are all represented herein by a single molecular formula, thepresent invention includes both the individual, isolated isomers andmixtures, including racemates thereof. Where stereospecific synthesistechniques are employed or optically active compounds are employed asstarting materials, individual isomers may be prepared directly; on theother hand, if a mixture of isomers is prepared, the individual isomersmay be obtained by conventional resolution techniques.

Preferred classes of compounds of the present invention are thosecompounds of formula (I) and salts, esters and other functionalderivatives thereof, in which:

(A) R¹ represents:

a hydrogen atom;

an alkyl group having 3 carbon atoms;

a benzyl group;

a substituted benzyl group having at least one substituent selected fromthe group consisting of alkyl groups having from 1 to 4 carbon atoms,alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, aminogroups, alkylamino-groups having from 1 to 4 carbon atoms, dialkylaminogroups in which each alkyl part has from 1 to 4 carbon atoms, hydroxygroups, alkoxycarbonyl groups having from 2 to 5 carbon atoms andaliphatic acylamino groups having from 1 to 5 carbon atoms;

a furylmethyl group; or

a thienylmethyl group;

(B) R² represents:

a substituted alkyl group having from 1 to 4 carbon atoms andsubstituted by 1 or 2 substituents selected from the group consisting ofphenyl groups, substituted phenyl groups, thienyl groups, furyl groups,substituted thienyl groups and substituted furyl groups, wherein thesubstituent or substituents on the phenyl group are selected from thegroup consisting of:

alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from1 to 4 carbon atoms, halogen atoms, hydroxy groups, amino groups,alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groupsin which each alkyl part has from 1 to 4 carbon atoms, alkoxycarbonylgroups having from 2 to 5 carbon atoms and aliphatic acylamino groupshaving from 1 to 5 carbon atoms;

and the substituent or substituents on the thienyl and furyl groups areselected from the group consisting of alkyl groups having from 1 to 4carbon atoms;

or a diarylamino group, in which each aryl part is a carbocyclicaromatic group which has from 6 to 10 ring carbon atoms and which isunsubstituted or is substituted by at least one substituent selectedfrom the group consisting of

alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from1 to 4 carbon atoms, halogen atoms, hydroxy groups, amino groups,alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groupsin which each alkyl part has from 1 to 4 carbon atoms, alkoxycarbonylgroups having from 2 to 5 carbon atoms and aliphatic acylamino groupshaving from 1 to 5 carbon atoms;

(C) R³ represents:

a carboxy group;

an alkoxycarbonyl group having from 2 to 5 carbon atoms;

a benzyloxycarbonyl group;

a substituted benzyloxycarbonyl group at least one substituent selectedfrom the group consisting of methyl, ethyl, methoxy and ethoxy groupsand fluorine and chlorine atoms;

a naphthylmethoxycarbonyl group;

a diphenylmethoxycarbonyl group;

an alkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from 1to 5 carbon atoms and the alkoxy part has from 1 to 4 carbon atoms;

a cycloalkanecarbonyloxyalkoxycarbonyl group in which the cycloalkanepart has from 5 to 7 carbon atoms and the alkoxy part has from 1 to 4carbon atoms;

an alkoxycarbonyloxyalkoxycarbonyl group in which each alkoxy part hasfrom 1 to 4 carbon atoms;

a cycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloalkylpart has from 5 to 7 carbon atoms and the alkoxy part has from 1 to 4carbon atoms;

a (5-phenyl- or 5-alkyl-2-oxo-1,3-dioxolen-4-yl)-methoxycarbonyl groupin which the alkyl part has from 1 to 4 carbon atoms;

a phthalidyloxycarbonyl group; or

a group of formula --CONHSO₂ R⁴ wherein R⁴ represents an alkyl grouphaving from 1 to 4 carbon atoms.

More preferred compounds of the present invention are those compounds offormula (I) and salts, esters and other functional derivatives thereof,in which:

(D) R¹ represents:

a hydrogen atom;

an isopropyl group;

a benzyl group;

a substituted benzyl group having at least one substituent selected fromthe group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy,ethoxycarbonyl, methoxycarbonyl, amino, methylamino, ethylamino,dimethylamino, diethylamino, formamido and acetamido groups andfluorine, chlorine and bromine atoms; or

a thienylmethyl group;

(E) R² represents:

a substituted alkyl group having from 1 to 4 carbon atoms and having 1or 2 substituents selected from the group consisting of:

phenyl groups;

substituted phenyl groups having at least one substituent selected fromthe group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy,methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino,dimethylamino, diethylamino, formamido and acetamido groups andfluorine, chlorine and bromine atoms;

furyl groups;

methyl-substituted furyl groups

thienyl groups; and

methyl-substituted thienyl groups;

a diphenylamino group; or

a substituted diphenylamino group having at least one substituentselected from the group consisting of methyl, ethyl, methoxy, ethoxy,hydroxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino,ethylamino, dimethylamino, diethylamino, formamido and acetamido groupsand fluorine, chlorine and bromine atoms;

(F) R³ represents:

a carboxy group;

an alkoxycarbonyl group having from 2 to 5 carbon atoms;

a benzyloxycarbonyl group;

an alkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from 1to 5 carbon atoms and the alkoxy part has 1 or 2 carbon atoms;

a cycloalkanecarbonyloxyalkoxycarbonYl group in which the cycloalkanepart has from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms;

a methoxycarbonyl or ethoxycarbonyl group which is substituted by analkoxycarbonyloxy group having from 2 to 5 carbon atoms;

a cycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloalkylpart has from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms;

a (5-phenyl-, 5-methyl- or 5-ethyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group;

a phthalidyloxycarbonyl group; or

a group of formula --CONHSO₂ R⁴, wherein R⁴ represents a methyl group oran ethyl group.

Still more preferred compounds of the present invention are thosecompounds of formula (I) and salts, esters and other functionalderivatives thereof, in which:

(G) R¹ and R² are independently selected from the group consisting ofbenzyl groups and substituted benzyl groups having at least onesubstituent selected from the group consisting of methyl, methoxy,hydroxy and acetamido groups and fluorine and chlorine atoms;

or

(H) R¹ represents a hydrogen atom, and R² represents:

a substituted alkyl group having from 1 to 4 carbon atoms and having 1or 2 substituents selected from the group consisting of:

phenyl groups;

substituted phenyl groups having at least one substituent selected fromthe group consisting of methyl, methoxy, hydroxy, dimethylamino andacetamido groups and fluorine and chlorine atoms;

furyl groups and thienyl groups;

a diphenylamino group; or

a substituted diphenylamino group having at least one substituentselected from the group consisting of methyl, methoxy, hydroxy,dimethylamino and acetamido and fluorine and chlorine atoms.

(I) R³ represents a carboxy group, a methoxycarbonyl group, anethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group, anethoxycarbonyloxymethoxycarbonyl group, a1-(ethoxycarbonyloxy)ethoxycarbonyl group, anisopropoxycarbonytoxymethoxycarbonyl group, a 1-(isopropoxycarbonyloxy)ethoxycarbonyl group, a(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group, aphthalidyloxycarbonyl group or a group of formula --CONHSO₂ R⁴, whereinR⁴ represents a methyl group.

The most preferred compounds of the present invention are thosecompounds of formula (I) and salts, esters and other functionalderivatives thereof, in which:

(J) R¹ represents a hydrogen atom, R² represents an alkyl group havingfrom 1 to 3 carbon atoms and substituted with 1 or 2 substituentsselected from the group consisting of:

substituted phenyl groups having at least one substituent selected fromthe group consisting of methyl, methoxy and hydroxy groups and fluorineand chlorine atoms;

furyl groups and thienyl groups;

(K) R³ represents a carboxy group, a methoxycarbonyl group or anethoxycarbonyl group;

(L) R² represents a 2-hydroxyisopropyl group or a 1-carboxyethyl grouphaving at least one substituent selected from the group consisting ofaryl groups as defined above and aromatic heterocyclic groups as definedabove.

Specific examples of the compounds of the present invention includethose of formula (I) in which R¹, R² and R³ are as shown in thefollowing Table 1. In the Table, the following abbreviations are used:

    ______________________________________                                        Ac               acetyl                                                       Bu               butyl                                                        Bz               benzyl                                                       Bzhy             benzhydryl                                                   Et               ethyl                                                        Fur              furyl                                                        Me               methyl                                                       Mod              (5-methyl-2-oxo-1,3-                                                          dioxolen-4-yl)methyl                                         Ph               phenyl                                                       Phth             phthalidyl                                                   Piv              pivaloyl                                                     Pr               propyl                                                       iPr              isopropyl                                                    Thi              thienyl                                                      ______________________________________                                    

                                      TABLE 1                                     __________________________________________________________________________    Cpd.                                                                          No. R.sup.1                                                                              R.sup.2       R.sup.3                                              __________________________________________________________________________    1   H      1,2-diPhEt    COOH                                                 2   H      Bzhy          COOH                                                 3   H      1,1-diPhEt    COOH                                                 4   Bz     Bz            COOH                                                 5   H      1,2-di(2-Thi)Et                                                                             COOH                                                 6   H      1,2-bis(4-FPh)Et                                                                            COOH                                                 7   H      1,2-bis(4-MePh)Et                                                                           COOH                                                 8   H      1,2-bis(4-MeOPh)Et                                                                          COOH                                                 9   H      1,2-bis(4-ClPh)Et                                                                           COOH                                                 10  H      di(2-Thi)CH-- COOH                                                 11  H      1,2-di(2-Thi)Et                                                                             COOMe                                                12  H      bis(4-FPh)CH--                                                                              COOH                                                 13  H      bis(4-MePh)CH--                                                                             COOH                                                 14  H      bis(4-MeOPh)CH--                                                                            COOH                                                 15  H      2-(4-MeOPh)-1-(2-Thi)Et                                                                     COOH                                                 16  H      2-(4-FPh)-1-(2-Thi)Et                                                                       COOH                                                 17  H      2-(4-MePh)-1-(2-Thi)Et                                                                      COOH                                                 18  H      2-(4-ClPh)-1-(2-Thi)Et                                                                      COOH                                                 19  H      1-(2-Fur)-2-PhEt                                                                            COOH                                                 20  H      2-Ph-1-(2-Thi)Et                                                                            COOH                                                 21  H      di(3-Thi)CH-- COOH                                                 22  H      2-(4-MePh)-1-PhEt                                                                           COOH                                                 23  H      2-(4-FPh)-1-(4-MePh)Et                                                                      COOH                                                 24  H      2-(4-MeOPh)-1-PhEt                                                                          COOH                                                 25  H      2-(4-FPh)-1-(4-MeOPh)Et                                                                     COOH                                                 26  H      1-Bz-4-PhBu   COOH                                                 27  H      4-ClBzhy      COOH                                                 28  H      4-MeOBzhy     COOH                                                 29  H      4-FBzhy       COOH                                                 30  H      4-F-4'-MeOBzhy                                                                              COOH                                                 31  H      4-MeBzhy      COOH                                                 32  H      2-Ph-1-(2-Thi)Et                                                                            COOMe                                                33  H      2-Ph-1-(2-Thi)Et                                                                            COOCH.sub.2 OPiv                                     34  H      2-Ph-1-(2-Thi)Et                                                                            COOCH(Me)OCOOEt                                      35  H      2-Ph-1-(2-Thi)Et                                                                            COOMod                                               36  H      2-Ph-1-(2-Thi)Et                                                                            COONa                                                37  H      1,1-diBzEt    COOH                                                 38  H      1,1-di(2-Thi)Et                                                                             COOH                                                 49  H      1,1-di(2-Thi)Et                                                                             COOMe                                                40  H      1,1-di(2-Thi)Et                                                                             COOCH.sub.2 OPiv                                     41  H      1,1-di(2-Thi)Et                                                                             COOCH(Me)OCOOEt                                      42  H      1,1-di(2-Thi)Et                                                                             COOMod                                               43  H      1,1-di(2-Thi)Et                                                                             COONa                                                44  H      Bzhy          COOMe                                                45  H      Bzhy          COOCH.sub.2 OPiv                                     46  H      Bzhy          COOCH(Me)OCOOEt                                      47  H      Bzhy          COOMod                                               48  H      Bzhy          COONa                                                49  H      1,2-diPhEt    COOEt                                                50  H      1,2-diPhEt    COOCH.sub.2 OPiv                                     51  H      1,2-diPhEt    COOCH(Me)OCOOEt                                      52  H      1,2-diPhEt    COOMod                                               53  H      1,2-diPhEt    COONa                                                54  H      1,2-diPhEt    COOPhth                                              55  H      1,1-diPhEt    COOMe                                                56  H      1,1-diPhEt    COOEt                                                57  H      1,1-diPhEt    COOCH.sub.2 OPiv                                     58  H      1,1-diPhEt    COOCH(Me)OCOOEt                                      59  H      1,1-diPhEt    COOMod                                               60  H      1,1-diPhEt    COOPhth                                              61  H      1,1-diPhEt    COONa                                                62  H      1-Bz-1-PhEt   COOH                                                 63  H      1,2-diPhPr    COOH                                                 64  4-HOBz 4-HOBz        COOH                                                 65  4-FBz  4-FBz         COOH                                                 66  H      1-Me-1-PhEt   COOH                                                 67  H      1-Me-1-(2-Thi)Et                                                                            COOH                                                 68  H      1-Me-1-(2-Thi)Et                                                                            COOMe                                                69  H      1-Me-1-(2-Thi)Et                                                                            COOCH.sub.2 OPiv                                     70  H      1-Me-1-(2-Thi)Et                                                                            COOCH(Me)OCOOEt                                      71  H      1-Me-1-(2-Thi)Et                                                                            COOMod                                               72  H      1-Me-1-PhEt   COOMe                                                73  H      1-Me-1-PhEt   COOCH.sub.2 OPiv                                     74  H      1-Me-1-PhEt   COOCH(Me)OCOOEt                                      75  H      1-Me-1-PhEt   COOMod                                               76  H      1,1-diMe-2-PhEt                                                                             COOH                                                 77  H      1-Me-1-(4-HOPh)Et                                                                           COOH                                                 78  H      1-Me-1-(4-FPh)Et                                                                            COOH                                                 79  H      1-Me-1-(4-NMe.sub.2 Ph)Et                                                                   COONa                                                80  H      di(2-Fur)CH-- COOH                                                 81  H      4,4'-diHOBzhy COOH                                                 82  H      1,2-bis(4-HOPh)Et                                                                           COOH                                                 83  H      1,2-bis(4-HOPh)-1-MeEt                                                                      COOH                                                 84  iPr    Bz            COOH                                                 85  Et     Bz            COOH                                                 86  Me     Bz            COOH                                                 87  iBu    Bz            COOH                                                 88  iPr    4-FBz         COOH                                                 89  iPr    4-ClBz        COOH                                                 90  iPr    4-MeBz        COOH                                                 91  iPr    4-MeOBz       COOH                                                 92  iPr    4-HOBz        COOH                                                 93  2-ThiMe                                                                              2-ThiMe       COOH                                                 94  2-ThiMe                                                                              Bz            COOH                                                 95  H      Bzhy          COOEt                                                96  H      Bzhy          COOCH.sub.2 OPiv                                     97  H      Bzhy          COOCH(Me)OCOOEt                                      98  H      Bzhy          COOMod                                               99  H      Bzhy          COONa                                                100 Bz     Bz            COOMe                                                101 Bz     Bz            COOEt                                                102 H      di(2-Thi)CH-- COOMe                                                103 H      di(2-Thi)CH-- COOEt                                                104 H      di(2-Thi)CH-- COOCH.sub.2 OPiv                                     105 H      di(2-Thi)CH-- COOCH(Me)OCOOEt                                      106 H      di(2-Thi)CH-- COOMod                                               107 H      di(2-Thi)CH-- COONa                                                108 H      2-(4-MePh)-1-PhEt                                                                           COOMe                                                109 H      2-(4-MePh)-1-PhEt                                                                           COOEt                                                110 H      2-(4-MePh)-1-PhEt                                                                           COOCH.sub.2 OPiv                                     111 H      2-(4-MePh)-1-PhEt                                                                           COOCH(Me)OCOOEt                                      112 H      2-(4-MePh)-1-PhEt                                                                           COOMod                                               113 H      2-(4-MePh)-1-PhEt                                                                           COONa                                                114 H      1,1-diPhEt    COOMe                                                115 H      1-Me-1-PhEt   COOEt                                                116 H      1-Me-1-PhEt   COOCH.sub.2 OPiv                                     117 H      1-Me-1-PhEt   COOCH(Me)OCOOEt                                      118 H      1-Me-1-PhEt   COOMod                                               119 H      1-Me-1-PhEt   COONa                                                120 H      1-Me-1-(2-Thi)Et                                                                            COOEt                                                121 H      1-Me-1-(2-Thi)Et                                                                            COOCH.sub.2 OPiv                                     122 H      1-Me-1-(2-Thi)Et                                                                            COOCH(Me)OCOOEt                                      123 H      1-Me-1-(2-Thi)Et                                                                            COOMod                                               124 H      1-Me-1-(2-Thi)Et                                                                            COONa                                                125 H      1,1-diMe-2-PhEt                                                                             COOMe                                                126 H      4,4'-diMeOBzhy                                                                              COOMe                                                127 H      4-HOBzhy      COOH                                                 128 H      4-HOBzhy      COOMe                                                129 H      4-HOBzhy      COOEt                                                130 H      4-HOBzhy      COOCH.sub.2 OPiv                                     131 H      4-HOBzhy      COOCH(Me)OCOOEt                                      132 H      4-HOBzhy      COOMod                                               133 H      4-HOBzhy      COONa                                                134 H      4-MeOBzhy     COOEt                                                135 H      4-MeOBzhy     COONa                                                136 H      4-MeOBzhy     COOMe                                                137 H      4-MeOBzhy     COOCH.sub.2 OPiv                                     138 H      4-MeOBzhy     COOCH(Me)OCOOEt                                      139 H      4-MeOBzhy     COOMod                                               140 H      4-ClBzhy      COOH                                                 141 H      4-ClBzhy      COOMe                                                142 H      1-(4-MeOPh)-1-MeEt                                                                          COOH                                                 143 H      1-(4-MeOPh)-1-MeEt                                                                          COOMe                                                144 H      1-(4-MeOPh)-1-MeEt                                                                          COOEt                                                145 H      1-(4-MeOPh)-1-MeEt                                                                          COOCH.sub.2 OPiv                                     146 H      1-(4-MeOPh)-1-MeEt                                                                          COOCH(Me)OCOOEt                                      147 H      1-(4-MeOPh)-1-MeEt                                                                          COOMod                                               148 H      1-(4-MeOPh)-1-MeEt                                                                          COONa                                                149 H      1-(3,5-diMeOPh)-1-MeEt                                                                      COOH                                                 150 H      1-(3,5-diMeOPh)-1-MeEt                                                                      COOMe                                                151 H      1-(4-FPh)-1-MeEt                                                                            COOEt                                                152 H      1-(4-FPh)-1-MeEt                                                                            COOCH.sub.2 OPiv                                     153 H      1-(4-FPh)-1-MeEt                                                                            COOCH(Me)OCOOEt                                      154 H      1-(4-FPh)-1-MeEt                                                                            COOMod                                               155 H      1-(4-FPh)-1-MeEt                                                                            COONa                                                156 H      1-(4-FPh)-1-MeEt                                                                            COOMe                                                157 H      1-(4-AcNHPh)-1-MeEt                                                                         COOH                                                 158 H      1-(4-AcNHPh)-1-MeEt                                                                         COOMe                                                159 H      Ph.sub.2 N--  COOH                                                 160 H      Ph.sub.2 N--  COOMe                                                161 H      Ph.sub.2 N--  COOEt                                                162 H      Ph.sub.2 N--  COOCH.sub.2 OPiv                                     163 H      Ph.sub.2 N--  COOCH(Me)OCOOEt                                      164 H      Ph.sub.2 N--  COOMod                                               165 H      Ph.sub.2 N--  COONa                                                166 H      1-Me-1-(3-MeOPh)Et                                                                          COOH                                                 167 H      1-Me-1-(3-MeOPh)Et                                                                          COOMe                                                168 H      1-Me-1-(2-MeOPh)Et                                                                          COOH                                                 169 H      1-Me-1-(2-MeOPh)Et                                                                          COOMe                                                170 H      2,2-diPhEt    COOH                                                 171 H      3,3-diPhPr    COOH                                                 172 H      Bzhy          COOEt                                                173 H      Bzhy          COOMe                                                174 H      Bzhy          COOCH.sub.2 OPiv                                     175 H      Bzhy          COOCH(Me)OCOOEt                                      176 H      Bzhy          COOMod                                               177 H      Bzhy          COONa                                                178 H      1-Me-1-(2-Fur)Et                                                                            COOH                                                 179 H      1-Me-1-(2-Fur)Et                                                                            COOMe                                                180 H      1-Me-1-PhEt   CONHSO.sub.2 Me                                      181 H      1-Me-1-(2-Thi)Et                                                                            CONHSO.sub.2 Me                                      182 H      1-Me-1-(4-MeOPh)Et                                                                          CONHSO.sub.2 Me                                      183 H      1-Me-1-(3-Thi)Et                                                                            CONHSO.sub.2 Me                                      184 H      1-Me-1-(4-NMe.sub.2 Ph)Et                                                                   CONHSO.sub.2 Me                                      185 H      1-Me-1-(4-FPh)Et                                                                            CONHSO.sub.2 Me                                      186 H      1-Me-1-(4-MePh)Et                                                                           CONHSO.sub.2 Me                                      187 H      1-Me-1-(4-ClPh)Et                                                                           CONHSO.sub.2 Me                                      188 H      Bzhy          CONHSO.sub.2 Me                                      189 H      Bzhy          CONHSO.sub.2 Et                                      190 H      1-Me-1-(4-NMe.sub.2 Ph)Et                                                                   COOH                                                 191 H      1-Me-1-(3-Thi)Et                                                                            COOH                                                 192 H      1-Me-1-(3,4-diMeOPh)Et                                                                      COOH                                                 193 H      1-Me-1-(4-ClPh)Et                                                                           COOH                                                 194 H      1-Me-1-(4-EtOPh)Et                                                                          COOH                                                 195 H      1-Et-1-PhPr   COOH                                                 196 H      1-Me-1-(4-MePh)Et                                                                           COOH                                                 197 H      1-Me-1-(3,4,5-triMeOPh)Et                                                                   COOMe                                                198 H      1-HOMe-1-(4-MeOPh)Et                                                                        COOH                                                 199 H      1-HOOC-1-(4-MeOPh)Et                                                                        COOH                                                 200 H      1-Me-1-(3,4,5-triMeOPh)Et                                                                   COOH                                                 201 H      1-Me-1-(3,5-diNMe.sub.2 Ph)Et                                                               COOH                                                 __________________________________________________________________________

Of these, preferred compounds are Compounds No. 1, 2, 4, 5, 8, 9, 12,14, 17, 19, 22, 27, 28, 29, 31, 33, 45, 48, 50, 64, 66, 67, 69, 73, 76,78, 79, 82, 86, 88, 127, 130, 140, 142, 145, 149, 152, 157, 159, 166,168, 178, 180, 182, 190, 191, 192, 193, 194, 195, 196, 197, 200 and 201,and more preferred compounds are Compounds No. 1, 2, 4, 5, 12, 14, 22,27, 28, 31, 64, 66, 67, 76, 78, 127, 142, 145, 149, 159, 166, 168, 178,190, 192, 194, 195, 197, 200 and 201.

The most preferred compounds are Compounds No.

1. 17-[N-(1,2-Diphenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid;

2. 17-[N-(Diphenylmethyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid;

14.17-[N-(4,4'-Dimethoxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid;

66.17-[N-(1-Methyl-1-phenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid;

67.17-{N-[1-Methyl-1-(2-thienyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;

78.17-{N-[1-(4-Fluorophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;

127. 17β-[N-(4-Hydroxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylic acid;

149.17-{N-[1-(3,5-Dimethoxyphenyl)-1-methylethyl]-carbamoyl}androsta-3,5-diene-3-carboxylicacid;

159. 17-[N-(Diphenylamino)carbamoyl]androsta-3,5-diene-3-carboxylicacid;

166.17-{N-[1-(3-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;

168.17-{N-[1-(2-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;

178.17-[N-(α,α-Dimethylfurfuryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid;

190.17-{N-[1-(4-N,N-Dimethylaminophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;

192.17-{N-[1-(3,4-Dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;

194.17-{N-[1-(4-Ethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid; and

200.17-{N-[1-Methyl-1-(3,4,5-trimethoxyphenyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;

and pharmaceutically acceptable salts and esters thereof.

The compounds of the present invention may be prepared by a variety ofmethods well known for the preparation of known compounds of this type.For example, in general terms, they can be prepared by hydrolysing acompound of formula (VI): ##STR4## (wherein R¹ and R² are as definedabove), to give the corresponding carboxylic acid of formula (Ia):##STR5## (wherein R¹ and R² are as defined above), and, if desired,converting the carboxy group at the 3-position to any other grouprepresented by R³ in the compound of formula (I), and, if desired,salifying or esterifying the compound of formula (Ia).

In more detail, starting from known or readily available startingmaterials, the compounds of the present invention may be prepared asillustrated in the following Reaction Scheme A: ##STR6##

In the above formulae:

R¹, R² and R³ are as defined above; and

R⁵ represents a carboxy-protecting group, preferably an alkyl grouphaving from 1 to 6 carbon atoms (such as those exemplified above inrelation to R¹), or a group of formula --SiR^(a) R^(b) R^(c) (whereinR^(a), R^(b) and R^(c) are as defined above).

In Step A1 of this Reaction Scheme, a compound of formula (III) isprepared by reacting a compound of formula (II) with a dialkylcyanophosphate (in which each alkyl group has from 1 to 6 carbon atoms)or a diaryl cyanophosphate (in which the aryl group may be as definedand exemplified above in relation to the substituents on R²) in an inertsolvent in the presence of an alkali metal cyanide, and then reactingthe resulting phosphoric acid ester with an acid.

There is no particular limitation on the alkali metal cyanide employed,and any alkali metal cyanides commonly used in reactions of this typemay equally be employed here. Examples of such compounds include lithiumcyanide, sodium cyanide and potassium cyanide, of which we preferlithium cyanide.

There is no likewise particular limitation on the nature of the dialkylor diaryl cyanophosphate employed, and examples include dimethylcyanophosphate, diethyl cyanophosphate, diphenyl cyanophosphate andditolyl cyanophosphate, of which we prefer diethyl cyanophosphate ordiphenyl cyanophosphate.

The acid employed in the second part of this step is also not criticalto the invention, and examples include Lewis acids, such as borontrifluoride, boron trifluoride-diethyl ether complexes, zinc chloride,aluminum chloride and tin tetrachloride, of which we prefer borontrifluoride or a boron trifluoride-diethyl ether complex.

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include: aromatichydrocarbons, such as benzene, toluene and xylene; ethers, such asdiethyl ether, tetrahydrofuran and dioxane; and halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride and chloroform; of these, we prefer the ethers forthe first reaction and aromatic hydrocarbons for the second reaction.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the first stage of thereaction at a temperature of from -20° to 50° C., more preferably from0° to 30° C., and to carry out the second stage of the reaction at atemperature of from -50° to 50° C., more preferably from -20° to 30° C.The time required for the reaction may likewise vary widely, dependingon many factors, notably the reaction temperature and the nature of thereagents. However, in most cases, a period of from 5 minutes to 5 hours,more preferably from 10 minutes to 1 hour, will normally suffice for thefirst stage of the reaction, whilst a period of from 30 minutes to 10hours, more preferably from 1 hour to 5 hours, will normally suffice forthe second stage of the reaction.

After completion of each of these reactions, the desired compounds canbe collected from the reaction mixture by conventional means. Forexample, one suitable recovery procedure comprises: removing the solventby distillation under reduced pressure; adding water to the residue; andextracting the mixture with a water-immiscible organic solvent, such asethyl acetate. The extract is then dried over anhydrous magnesiumsulfate, after which the solvent is removed by distillation, to give thedesired compound. If necessary, the resulting compounds can be furtherpurified by conventional means, such as recrystallization or the variouschromatography techniques, notably column chromatography. However, if italso possible, in appropriate cases, to use the product of the first orsecond stage in the next reaction without any intermediate isolation orpurification.

The compound of formula (II) and the compound of formula (II'), whichare used as starting materials in Reaction Schemes A and B,respectively, are known or can be prepared according to known methods[e.g., as described in J. Med. Chem., 27, 1690 (1984); and J. Med.Chem., 29, 2298 (1986)].

In Step A2, a compound of formula (IV) is prepared by hydrolysing acompound of formula (III) with a base in an inert solvent.

There is no particular restriction on the nature of the base, providedthat it has no adverse effect on other parts of the molecule. Examplesof suitable bases include: alkali metal hydroxides, such as lithiumhydroxide, sodium hydroxide and potassium hydroxide; and alkali metalcarbonates, such as lithium carbonate, sodium carbonate and potassiumcarbonate; of these, we prefer the alkali metal hydroxides.

The reaction is normally and preferably effected in the presence of aninert solvent, the nature of which is not critical, provided that it hasno adverse effect upon the reaction and that it can dissolve thereagents, at least to some extent. Examples of suitable solventsinclude: ethers, such as tetrahydrofuran and dioxane; alcohols, such asmethanol, ethanol and butanol; glycols and glycol ethers, such asethylene glycol, propylene glycol and ethylene glycol dimethyl ether;water; and mixtures of any two or more of these solvents; of these, weprefer the alcohols.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from 0° to 150° C., more preferably from 30°to 100° C. The time required for the reaction may likewise vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents. However, in most cases, a period of from 1 hourto 50 hours, more preferably from 3 hours to 20 hours, will normallysuffice.

After completion of the reaction, the desired compound can be collectedfrom the reaction mixture by conventional means. For example, onesuitable recovery procedure comprises: removing the solvent bydistillation under reduced pressure; adding an aqueous acid solution,such as dilute hydrochloric acid, to the residue to make it acidic;extracting the resulting mixture with a water-immiscible organicsolvent, such as methylene chloride; drying the extract over anhydrousmagnesium sulfate; and removing the solvent by distillation, to give thedesired compound. If necessary, the resulting compound can be furtherpurified by conventional means, such as recrystallization or the variouschromatography techniques, notably column chromatography.

Steps A1 and A2 can be carried out in the reverse order, if desired,that is, the introduction of a cyano group (Step A1) may take placebefore or after the hydrolysis (Step A2).

In Step A3, a compound of formula (VI) is prepared by reacting acompound of formula (IV) or a reactive derivative thereof with acompound of formula (V). This reaction may be carried out usingconventional methods well known in the field of peptide synthesis, suchas the acyl halide method, the azide method, the active ester method,the mixed acid anhydride method and the condensation method.

The acyl halide method may be carried out as follows: the compound offormula (IV) is reacted with halogenating agent in an inert solvent at asuitable temperature, and then the resulting compound is reacted with anamine compound of formula (V) according to the method as described in,for example, Japanese Patent Application Kokai No. Sho 54-145669(=European Patent Publication No. 4949A), the disclosure of which isincorporated herein by reference.

Of the above methods, the azide method may be carried out as follows:the compound of formula (IV) or an ester thereof is reacted withhydrazine in an inert solvent (e.g. dimethylformamide) at a suitabletemperature, preferably about room temperature, to give an amino acidhydrazide, which is then reacted with a nitrous acid compound to convertit to an azide compound. This azide compound is then reacted with anamine compound of formula (V).

There is no particular restriction on the nature of the nitrous acidcompound employed, and any such compound commonly employed in this typeof reaction may equally be used here. Examples of such compoundsinclude: alkali metal nitrites, such as sodium nitrite; and alkylnitrites, such as isoamyl nitrite.

The reaction of the hydrazide with the nitrous acid compound ispreferably carried out in an inert solvent, the nature of which is notcritical, provided that it has no adverse effect upon the reaction andthat it can dissolve the reagents, at least to some extent. Examples ofsuitable solvents include: amides, such as dimethylformamide anddimethylacetamide; sulfoxides, such as dimethyl sulfoxide; andpyrrolidones, such as N-methylpyrrolidone. The subsequent step ofreaction with an amine compound of formula (V) is usually carried out inone reaction mixture. The reactions will take place over a wide range oftemperatures, and the precise reaction temperature chosen is notcritical to the invention. In general, we find it convenient to carryout the reaction with the nitrous acid compound at a temperature in therange of from -50° to 0° C. and that with the amine compound of formula(V) at a temperature in the range of from -10° to 10° C. The timerequired for the reaction may likewise vary widely, depending on manyfactors, notably the reaction temperature and the nature of thereagents. However, in most cases, a period of from 5 minutes to 1 hourwill normally suffice for the former step and a period of from 10 hoursto 5 days will normally suffice for the latter step.

The active ester method may be carried out according to the methoddescribed in Japanese Patent Application Kokai No. Hei 2-172,999(=European Patent Publication No. 478 066A), Japanese Patent ApplicationKokai No. Hei 4-288,096 (=European Patent Publication No. 367 502A), orEuropean Patent Publication No. 85301122, the disclosures of which areincorporated herein by reference, by reacting the compound of formula(IV) with an active esterifying agent to give an active ester, which isthen reacted with the amine compound of formula (V).

These two reactions are preferably carried out in an inert solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: aromatichydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride and chloroform; ethers, such as diethyl ether andtetrahydrofuran; amides, such as dimethylformamide anddimethylacetamide; nitriles, such as acetonitrile; and amines, such aspyridine and triethylamine.

There is no particular restriction on the nature of the activeesterifying agent employed, and examples of suitable compounds include:N-hydroxy compounds, such as N-hydroxysuccinimide,1-hydroxybenzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide; anddisulfide compounds, such as dipyridyl disulfide. The activeesterification reaction is preferably carried out in the presence of acondensing agent, such as dicyclohexylcarbodiimide, carbonyldiimidazoleor triphenylphosphine.

The reactions will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the active esterificationreaction at a temperature in the range of from -10° to 100° C. and thereaction between the active ester compound and the amine of formula (V)at about room temperature.. The time required for the reactions maylikewise vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents. However, in most cases, aperiod of from 30 minutes to 80 hours will normally suffice for eachreaction.

These reactions can also be carried out in the presence ofdimethylaminopyridine.

The mixed acid anhydride method is carried out by preparing a mixed acidanhydride of the compound of formula (IV), and then reacting the mixedacid anhydride with the amine of formula (V).

The reaction for preparing the mixed acid anhydride can be accomplishedby reacting the compound of formula (IV) with an agent capable offorming a mixed acid anhydride, for example: C₁ -C₆ alkyl haloformate,such as ethyl chloroformate or isobutyl chloroformate; a C₂ -C₅ alkanoylhalide, such as pivaloyl chloride; a di(C₁ -C₆) alkyl cyanophosphate,such as diethyl cyanophosphate; or a diaryl cyanophosphate, such asdiphenyl cyanophosphate. The reaction is normally and preferably carriedout in an inert solvent (e.g. one or more of the above-mentionedhalogenated hydrocarbons, amides and ethers).

The reaction is also preferably carried out in the presence of anorganic amine, such as triethylamine or N-methylmorpholine.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from -10° to 50° C. The time required forthe reaction may likewise vary widely, depending on many factors,notably the reaction temperature and the nature of the reagents.However, in most cases, a period of from 30 minutes to 20 hours willnormally suffice.

The reaction between the resulting mixed acid anhydride and the amine offormula (V) is preferably carried out in an inert solvent (e.g. one ormore of the above-mentioned amides and ethers) in the presence of anorganic amine, such as triethylamine, N,N-dimethylaminopyridine orN-methylmorpholine, at a suitable temperature, for example a temperatureof from 0° to 80° C.; a period of from 1 to 30 hours will normallysuffice for this reaction.

This reaction can also be carried out by reacting the compound offormula (IV), the amine compound of formula (V) and agent for formingthe mixed acid anhydride simultaneously.

The condensation method may be carried out by reacting the compound offormula (IV) and the amine of formula (V) directly in the presence of acondensing agent, such as dicyclohexylcarbodiimide, carbonyldiimidizoleor 1-methyl-2-chloro-pyridinium iodide/triethylamine. This reaction iscarried out in the same manner as described above for preparing theactive ester.

A compound of formula (VI) may also be prepared easily and in a goodyield by reacting a compound of formula (IV) with an amine of formula(V) in an inert solvent in the presence of a base, and in the presenceof a sulfonyl compound of formula:

    R.sup.d --SO.sub.2 X or (R.sup.d --SO.sub.2).sub.2 O

(wherein R^(d) represents a C₁ -C₆ alkyl group, a trifluoromethyl group,a camphyl group, an isocyano group or a C₆ -C₁₀ aryl group which may beunsubstituted or may be substituted by a C₁ -C₆ alkyl groups, C₁ -C₆alkoxy group or a halogen atom, and X represents a halogen atom.).

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include:aliphatic hydrocarbons, such as hexane; aromatic hydrocarbons, such asbenzene, toluene and xylene; ethers, such as diethyl ether,tetrahydrofuran, dioxane and dimethoxyethane; amides, such asdimethylformamide, dimethylacetamide and hexamethylphosphoric triamide;sulfoxides, such as dimethyl sulfoxide; and halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as methylenechloride, chloroform and dichloroethane; of these, we prefer thehalogenated hydrocarbons.

Alternatively, a large excess of a liquid amine, such as triethylamineor pyridine, can be used also as solvent, and this may also serve as thebase.

There is no particular limitation on the base employed, and any basescommonly used in reactions of this type may equally be employed here.Examples of such compounds include organic amines such as triethylamine,tripropylamine, tributylamine diisopropylethylamine,N,N-dimethylaniline, N,N-diethylaniline, pyridine,4-(N,N-dimethylamino)pyridine, quinoline,1,5-diazabicyclo[4.3.0]nona-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), of which we prefer triethylamine,N,N-diethylaniline or pyridine. It is also possible to use two or moreof the above bases simultaneously in this reaction.

Preferred compounds of formula R^(d) --SO₂ X include methanesulfonylchloride, methanesulfonyl bromide, ethanesulfonyl chloride,propanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonylchloride, 2,4,6-trimethylbenzenesulfonyl chloride, chlorobenzenesulfonylchloride, bromobenzenesulfonyl chloride, methoxybenzenesulfonylchloride, camphorsulfonyl chloride and chlorosulfonyl isocyanate, ofwhich methanesulfonyl chloride, benzenesulfonyl chloride,toluenesulfonyl chloride and camphorsulfonyl chloride are morepreferred.

Preferred compounds of formula (R^(d) --SO₂)₂ O include methanesulfonicacid anhydride, trifluoromethanesulfonic acid anhydride, ethanesulfonicacid anhydride, benzenesulfonic acid anhydride, toluenesulfonic acidanhydride, chlorobenzenesulfonic acid anhydride and camphorsulfonic acidanhydride, of which methanesulfonic acid anhydride,trifluoromethanesulfonic acid anhydride, benzenesulfonic acid anhydrideand toluenesulfonic acid anhydride are more preferred.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -70° to 50° C., more preferably from -50° to 30° C.The time required for the reaction may likewise vary widely, dependingon many factors, notably the reaction temperature and the nature of thereagents. However, in most cases, a period of from 15 minutes to 20hours, more preferably from 30 minutes to 10 hours, will normallysuffice for the reaction.

This reaction may more preferably be carried out by dissolving thecompound of formula (IV) and from 1 to 10 equivalents of a base in aninert solvent, and then adding from 1 to 5 equivalents of the sulfonylcompound and from 1 to 5 equivalents of the amine of formula (V) eitherin that order or in the reverse order to this mixture.

The corresponding amide compounds of formula (VI) may also be obtainedby the above reaction, but using dimethylformamide-phosphoryloxychloride or a Vilsmeier reagent, such aschloromethylenedimethyliminium chloride, instead of the sulfonylcompound.

This reaction may more preferably be carried out by dissolving thecompound of formula (IV) and from 1 to 5 equivalents of a Vilsmeierreagent in an inert solvent, and then adding from 1 to 10 equivalents ofbase and from 1 to 5 equivalents of the amine of formula (V) to thismixture.

In Step A4, the compound of formula (Ia), which is a compound (I) inwhich R³ represents a carboxy group, is prepared by hydrolizing thecompound of formula (VI). If desired, this may be converted in Step A5to any other group included in the definition of R³ by protecting thecarboxy group of the resulting carboxylic acid or by sulfonylamidatingthe resulting carboxylic acid.

The hydrolysis in Step A4 may be carried out by reacting the compound offormula (VI) with a base in an inert solvent. Examples of the base andinert solvent which may be employed are substantially the same as thoseused in Step A2 above; however, the preferred inert solvent is a glycol.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from 50° to 250° C., more preferably from100° to 200° C. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, in most cases, a period of from 3hours to 50 hours, more preferably from 6 hours to 20 hours, willnormally suffice.

After completion of the reaction, the desired compound can be collectedfrom the reaction mixture by conventional means. For example, onesuitable recovery procedure comprises: removing the solvent bydistillation under reduced pressure; and adding an aqueous acid, such asdilute hydrochloric acid, to the residue to make it acidic. Theresulting mixture may then be extracted with a water-immiscible organicsolvent, such as methylene chloride. After the extract has been driedover anhydrous magnesium sulfate, the solvent is distilled off to givethe desired compound. If necessary, the resulting compounds can befurther purified by conventional means, such as recrystallization or thevarious chromatography techniques, notably column chromatography.

If R¹ or R² includes an alkanoylamino group, these may both behydrolyzed in the course of this hydrolysis reaction. In this case, thecorresponding amino compound can be converted to an alkanoyl amidocompound, if desired, by conventional means. This reaction may becarried out by reacting the corresponding amino compound with analkanoyl halide (such as acetyl chloride, acetyl bromide, propionylchloride, butyryl chloride or isobutyryl chloride) or with a mixed acidanhydride with formic acid or acetic acid, or with an acid anhydride(such as acetic anhydride, propionic anhydride, butyric anhydride orisobutyric anhydride). The reaction may be carried out in the samemanner as described for the reaction of the mixed acid anhydride withthe amine in Step A3.

Also, if R¹ or R² includes an alkoxycarbonyl group, these may both behydrolyzed to give a corresponding carboxylic acid. If desired, this canbe converted to an alkyl ester by a conventional esterificationreaction, which may be carried out in the same manner as thecarboxy-protecting reaction described below, wherein about oneequivalent of an esterification agent is used, and the resulting mixtureis separated to obtain the desired compound.

The carboxy-protecting reaction may be carried out in the presence of anorganic or inorganic base by methods well known in the art of syntheticorganic chemistry. For example, it is normally and preferably carriedout in an inert solvent, the nature of which is not critical, providedthat it has no adverse effect upon the reaction and that it can dissolvethe reagents, at least to some extent. Examples of suitable solventsinclude: amides, such as N,N-dimethylformamide or N,N-dimethylacetamide;halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons,such as methylene chloride; and ethers, such as tetrahydrofuran ordioxane. Most preferably, it is carried out by reacting an alkali metalsalt, such as the sodium salt or the potassium salt, of thecorresponding carboxylic acid of formula (Ia) with a compound of formula(VIII):

wherein:

R⁶ represents

a C₁ -C₆ alkyl group,

a C₁ -C₆ haloalkyl group,

a C₁ -C₆ hydroxyalkyl group,

an alkoxyalkyl group in which the alkoxy and alkyl parts both have from1 to 6 carbon atoms,

an alkoxyalkoxyalkyl group in which the alkoxy and alkyl parts all havefrom 1 to 6 carbon atoms,

a phenacyl group,

an alkoxycarbonylalkyl group in which the alkoxy and alkyl parts bothhave from 1 to 6 carbon atoms,

a C₁ -C₆ cyanoalkyl group,

a C₁ -C₆ alkylthiomethyl group,

a C₆ -C₁₀ arylthiomethyl group, in which the aryl group may be asdefined and exemplified above in relation to the aryl groups which maybe substituents on the substituted alkyl groups represented by R¹,

an alkylsulfonylalkyl group in which the alkyl parts both have from 1 to6 carbon atoms and which is optionally substituted with a halogen atom,

an arylsulfonylalkyl group, in which the aryl group may be as definedand exemplified above in relation to the aryl groups which may besubstituents on the substituted alkyl groups represented by R¹, and ispreferably unsubstituted or is an alkyl-substituted aryl group, and thealkyl part has from 1 to 6 carbon atoms,

a C₇ -C₁₃ aralkyl group,

a C₆ -C₁₀ aryl group, e.g. as defined and exemplified above in relationto the aryl groups which may be substituents on the substituted alkylgroups represented by R¹,

a group of formula --SiR^(a) R^(b) R^(c) (wherein R^(a), R^(b) and R^(c)are as defined and exemplified above),

an alkanoyloxyalkyl group, in which the alkanoyl and alkyl parts bothhave from 1 to 6 carbon atoms,

a cycloalkanecarbonyloxyalkyl group, in which the cycloalkane part hasfrom 5 to 7 ring carbon atoms and the alkyl part has from 1 to 6 carbonatoms,

an alkoxycarbonyloxyalkyl group, in which the alkoxy and alkyl parts allhave from 1 to 6 carbon atoms,

a cycloalkyloxycarbonyloxyalkyl group, in which the cycloalkyl part hasfrom 5 to 7 ring carbon atoms and the alkyl part has from 1 to 6 carbonatoms,

a [5-aryl- or 5-alkyl-2-oxo-1,3-dioxolen-4-yl]methyl group in which thearyl part may be as defined and exemplified above in relation to thearyl groups which may be substituents on the substituted alkyl groupsrepresented by R¹, and is preferably unsubstituted or is analkyl-substituted aryl group, and the alkyl part has from 1 to 6 carbonatoms,

or a phthalidyl group; and

Y represents a halogen atom (such as a chlorine, bromine or iodine atom)or a sulfonyloxy group (such as a methanesulfonyloxy, ethanesulfonyloxy,p-toluenesulfonyloxy or trifluoromethanesulfonyloxy group).

Alternatively, if the carboxy-protecting group is an alkyl group, theprotecting reaction may be carried out by reacting the correspondingcarboxylic acid with a di-C₁ -C₆ alkyl sulfate, such as dimethyl sulfateor diethyl sulfate, or with a diazo C₁ -C₆ alkane, such as diazomethane,diazoethane or diazopropane.

Examples of suitable bases include: alkali metal hydroxides, such aslithium hydroxide, sodium hydroxide and potassium hydroxide; alkalimetal carbonates, such as lithium carbonate, sodium carbonate andpotassium carbonate; and organic amines, such as triethylamine,N,N-dimethylaminopyridine or N-methylmorpholine.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from -20° to 50° C., more preferably from 0°to 30° C. The time required for the reaction may likewise vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents. However, in most cases, a period of from 30minutes to 5 hours, more preferably from 1 hour to 3 hours, willnormally suffice.

After completion of the reaction, the desired compound can be collectedfrom the reaction mixture by conventional means. For example, onesuitable recovery procedure comprises: removing the solvent bydistillation under reduced pressure; adding water to the residue; andextracting the resulting mixture with a water-immiscible organicsolvent, such as ethyl acetate. The extract may then be dried overanhydrous magnesium sulfate, after which the solvent is distilled off togive the desired compound. If necessary, the resulting compounds can befurther purified by conventional means, such as recrystallization or thevarious chromatography techniques, notably column chromatography.

The sulfonylamidation reaction may be carried out by reacting thecorresponding carboxylic acid with an active esterifying agent toprepare an active ester, and then reacting this active ester with acompound of formula (IX):

    MHNSO.sub.2 R.sup.4                                        (IX)

wherein R⁴ is as defined above; and M represents an alkali metal, suchas sodium or potassium.

The reaction for preparing the active ester may be carried out in thesame manner as described for the corresponding reaction in the Step A3above. The compound of formula (IX) may be prepared by conventionalprocedures, for example by reacting the corresponding sulfonamide withan alkali metal alkoxide, such as sodium methoxide, sodium ethoxide orpotassium t-butoxide, at a suitable temperature, e.g. at about roomtemperature, for an appropriate period, e.g. from 10 minutes to 3 hours,normally in an inert solvent, such as one of those suggested hereafterfor the reaction between the active ester and the compound of formula(IX).

The reaction between the active ester and the compound of formula (IX)may be carried out by reacting these compounds in an inert solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction and that it can dissolve the reagents, at least tosome extent. Examples of suitable solvents include: amides, such asN,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorictriamide; sulfoxides, such as dimethyl sulfoxide; and ethers, such astetrahydrofuran and dioxane.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from -20° to 100° C., more preferably from0° to 50° C. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, in most cases, a period of from 5minutes to 10 hours, more preferably from 10 minutes to 3 hours, willnormally suffice.

After completion of the reaction, the desired compound can be collectedfrom the reaction mixture by conventional means. For example, onesuitable recovery procedure comprises: removing the solvent bydistillation under reduced pressure; adding water to the residue; andextracting the resulting mixture with a water-immiscible organicsolvent, such as ethyl acetate. After the extract has been dried overanhydrous magnesium sulfate, the solvent may be distilled off, to givethe desired compound. If necessary, the resulting compounds can befurther purified by conventional means, such as recrystallization or thevarious chromatography techniques, notably column chromatography.

Compounds in which R² represents an alkyl group having a hydroxy orcarboxy substituent in addition to an aryl or aromatic substituent canbe prepared by the same procedures as described in the above steps, butusing the corresponding amine compound of formula (V) in Step A3; suchcompounds may also be prepared by oxidation in vivo as a result of thenormal mammalian metabolism.

An alternative method of preparing the compound of formula (VI),prepared as described above in Step A3, is shown in the followingReaction Scheme B: ##STR7##

In the above formulae, R¹ and R² are as defined above.

In Step B1, a compound of formula (VII) is prepared by reacting acompound of formula (II') with an amine compound of formula (V). Thisreaction is essentially the same as, and may be carried out using thesame reagents and reaction conditions as in, Step A3 of Reaction SchemeA.

In Step B2, a compound of formula (VI) is prepared by cyanizing thecompound of formula (VII). This reaction is essentially the same as, andmay be carried out using the same reagents and reaction conditions asin, Step A1 of Reaction Scheme A.

A compound (VI') of the formula: ##STR8## (wherein R and R' may be thesame or different from each other and each represents a hydrogen atom ora C₁ -C₆ alkyl group, such as those described and exemplified above inrelation to R¹) can be prepared by reacting a compound (II') with acompound of formula (V'):

    HNRR'                                                      (V')

(wherein R and R' are as defined above) as described in Step B1 and StepB2 of Reaction Scheme B. This compound of formula (VI') can be convertedby hydrolysis to a compound of formula (X): ##STR9## (wherein R and R'are as defined above). Accordingly, the compound of formula (VI') is agood intermediate for preparing the compound of formula (X). Thisreaction is essentially the same as that of Step A4 in Reaction Scheme Aand may be carried out using the same reagents and reaction conditions.

Preferred compounds of formula (VI') are those in which R represents ahydrogen atom and R' represents a C₁ -C₄ alkyl group, or in which R andR' are the same or different from each other and each represents a C₁-C₄ alkyl group, and more preferred compounds are those wherein Rrepresents a hydrogen atom, and R' represents a t-butyl group, or R andR' are the same and each represents an ethyl or isopropyl group.

The compounds (VI) and (VI') are novel compounds useful as intermediatesin the preparation of the compounds (I) and other active compounds ofthis type and thus also form part of the present invention.

The amine compound of formula (V), used as a starting material invarious of the above reactions, is known or may be prepared by knownmethods [e.g. Synthesis, 593 (1976); J. Org. Chem., 36, 305 (1971);Angew. Chem., 82, 138 (1970); Synthesis, 24 (1978); Synthetic Commun.,18, 777 (1988); Synthetic Commun., 18, 783 (1988); Organic Reaction, 3,337 (1946); Org. Synthesis, 51, 48 (1971); Tetrahedron, 30, 2151 (1974);J. Org. Chem., 37, 188 (1972)].

The amine compound of formula (V) wherein R² represents an alkyl grouphaving a hydroxy or carboxy substituent in addition to an aryl oraromatic heterocyclic substituent can be prepared by conventional meanswell known in the art.

For example, certain of the amine compounds of formula (V) may beprepared as shown in the following Schemes C, D and E: ##STR10##

In these formulae:

R⁶ and R⁷ are the same or different and may be any of the aryl groupsdefined and exemplified above in relation to R² ;

R⁸ represents an alkyl group having from 1 to 6 carbon atoms, as definedand exemplified above in relation to R¹ ; and

R⁹ represents an ester residue, for example as described above inrelation to protecting groups for R³, but preferably an alkyl group.

The reaction in Reaction Scheme C may be carried out using titaniumtrichloride, following the method described in Synthetic Communications,18, page 777 (1988).

The reactions in Reaction Scheme D comprise a Grignard reaction, theazidation of the hydroxy group in the resulting compound (XV), andreduction, in that order, according to the method described inSynthesis, page 24 (1978).

The reactions in Reaction Scheme E comprise an active carbonategeneration reaction, an acid azide formation reaction, an isocyanateformation reaction, and hydrolysis of the isocyanate, in that orderaccording to the method described in Journal of Organic Chemistry, 45,page 415 (1980).

A further alternative method of preparing the compounds of formula (I)from the compounds of formula (VI) is shown in the following ReactionScheme F: ##STR11##

In the above formulae, R¹, R² and R³ are as defined above.

In Step F1, a compound of formula (XXII) is prepared by reducing thecyano group of the compound of formula (VI) to yield an aldehyde group.

There is no particular limitation on the nature of the reducing agentemployed, and any reducing agent commonly used in reactions of this typemay equally be employed here. Examples of such reducing agents includereducing agents of the organic aluminum hydride type, such asdi(isobutyl)aluminum hydride and di(methoxyethoxy)aluminum sodiumdihydride.

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include:aliphatic hydrocarbons, such as hexane and heptane; aromatichydrocarbons, such as benzene, toluene and xylene; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane,diethylene glycol dimethyl ether and dioxane; halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as methylenechloride, tetrachloromethane, dichloroethane and chloroform; and amides,such as formamide, dimethylformamide, dimethylacetamide,hexamethylphosphoric triamide.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -100° to 30° C., more preferably from -10° to 20° C.The time required for the reaction may likewise vary widely, dependingon many factors, notably the reaction temperature, the startingmaterials, the solvent employed and the nature of the reagents. However,in most cases, a period of from 30 minutes to 10 hours, more preferablyfrom 1 hour to 5 hours, will normally suffice for the reaction.

After completion of the reaction, the desired compound (XXII) can becollected from the reaction mixture by conventional means. For example,one suitable recovery procedure comprises: adding water for hydrolysis;if appropriate, adjusting the pH of the mixture to a value in the rangeof from acidity or neutrality; if there is a precipitate, removing theprecipitate by filtration; adding water to the residue; and extractingthe mixture with a water-immiscible organic solvent, such as ethylacetate. The extract is then dried over anhydrous magnesium sulfate,after which the solvent is removed by distillation, to give the desiredcompound. If necessary, the resulting compounds can be further purifiedby conventional means, such as recrystallization or the variouschromatography techniques, notably column chromatography.

In Step F2, a compound of formula (I), which is a compound of thepresent invention, is prepared by oxidizing the aldehyde group of thecompound of formula (XXII) to a carboxy group, and then protecting orsulfonylamidating the carboxy group obtained, in the same manner asdescribed in Step A4 of Reaction Scheme A.

There is no particular limitation on the nature of the oxidizing agentemployed, and any oxidizing agent commonly used in oxidizing reactionsfor converting an aldehyde group to a carboxy group may equally beemployed here. Examples of such compounds include: inorganic metaloxidizing agents, for example manganese oxides (such as potassiumpermanganate or manganese dioxide), ruthenium oxides (such as rutheniumtetraoxide), selenium compounds (such as selenium dioxide), ironcompounds (such as iron chloride), osmium compounds (such as osmiumtetraoxide), silver compounds (such as silver oxide), chromic acidcompounds (such as potassium chromate, chromic anhydride-sulfuric acidcomplex or chromic anhydride-pyridine complex), and cerium compounds[such as cerium ammonium nitrate (CAN)]; and inorganic oxidizing agents,for example halogen molecules (such as chlorine molecules, brominemolecules and iodine molecules), periodic acids (such as sodiumperiodate), ozone, aqueous hydrogen peroxide, nitrous acid compounds(such as nitrous acid), chlorite compounds (such as potassium chloriteand sodium chlorite), and persulfuric acid compounds (such as potassiumpersulfate and sodium persulfate). Of these, the chromic acid compounds(such as potassium chromate, chromic anhydride-sulfuric acid complex andchromic anhydride-pyridine complex), cerium compounds [such as ceriumammonium nitrate (CAN)], chlorite compounds (such as potassium chloriteand sodium chlorite), and silver compounds (such as silver oxide) aremore preferred.

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include: aromatichydrocarbons, such as benzene, toluene and xylene; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane,diethylene glycol dimethyl ether and dioxane; halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as methylenechloride, tetrachloromethane, dichloroethane and chloroform; amides,such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; sulfoxides, such as dimethylsulfoxide;alcohols, such as methanol, ethanol, propanol, isopropanol, butanol,isobutanol and isoamyl alcohol; dilute aqueous acids, such as aqueoussulfuric acid; aqueous bases, such as aqueous sodium hydroxide; water;ketones, such as acetone and methyl ethyl ketone; organic bases, such aspyridine; and nitriles, such as acetonitrile.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -10° to 30° C., more preferably from 0° to aboutroom temperature. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature, thestarting materials, the solvent employed and the nature of the reagents.However, in most cases, a period of from 10 minutes to 10 hours, morepreferably from 30 minutes to 5 hours, will normally suffice for thereaction.

In the oxidation reaction mentioned above, the reaction may beaccelerated by adding a phase transfer catalyst, such as triethylbenzylammonium chloride or tributylbenzyl ammonium bromide, to the reactionmixture.

After completion of the reaction, the desired compound of formula (I)can be collected from the reaction mixture by conventional means. Forexample, one suitable recovery procedure comprises: if appropriate,adjusting the pH of the mixture to a value in the range of from acidityor neutrality; if there is precipitate, removing the precipitate byfiltration; adding water to the residue; and extracting the mixture witha water-immiscible organic solvent, such as ethyl acetate. The extractis then dried over anhydrous magnesium sulfate, after which the solventis removed by distillation, to give the desired compound. If necessary,the resulting compounds can be further purified by conventional means,such as recrystallization or the various chromatography techniques,notably column chromatography.

A still further alternative method of preparing the compound of thisinvention (I) from the compound (VII) is shown in the following ReactionScheme G: ##STR12##

In the above formulae, R¹, R², R³ and Y are as defined above, and R^(5')represents an alkyl group having from 1 to 10, preferably from 1 to 8,and more preferably from 1 to 6, carbon atoms, which may be the same asdefined above in relation to R⁵, or a cycloalkyl group having from 5 to7 carbon atoms.

In Step G1, a compound of formula (XXIII) is prepared by replacing thecarbonyl group of a compound of formula (VII) with the leaving group Yin the presence of base.

There is no particular limitation on the nature of the reagent used forthe introduction of the group Y, and any reagent commonly used inreactions of this type may equally be employed here. Examples of suchcompounds include: trifluoromethanesulfonylating agents, such astrifluoromethanesulfonic anhydride andN,N-di(trifluoromethanesulfonyl)anilide; phosphorus trihalides, such asphophorus trichloride, phosphorus tribromide and phosphorus triiodide;phosphorus pentahalides, such as phosphorus pentachloride, phosphoruspentabromide and phosphorus pentaiodide; organic acyl halides, such asoxalyl chloride; and phosphorus oxyhalides, such as phosphorusoxychloride, phosphorus oxybromide and phosphorus oxyiodide. Of these,we prefer the trifluoromethanesulfonylating agents.

There is no particular limitation on the nature of the base employed,and any bases commonly used in reactions of this type may equally beemployed here. Examples of such compounds include: organic amines suchas triethylamine, tripropylamine, tributylamine, diisopropylethylamine,N,N-dimethylaniline, N,N-diethylaniline, pyridine, N-methylmorpholine,2,6-di(t-butyl)-4-methylpyridine, 4-(N,N-dimethylamino)pyridine,quinoline, 1,5-diazabicyclo [4.3.0]nona-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and organic-metal bases, such as butyllithium,lithium diisopropylamide and lithium bis(trimethylsilyl) amide.

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include: aromatichydrocarbons, such as benzene, toluene and xylene; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane,diethylene glycol dimethyl ether and dioxane; halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as methylenechloride, tetrachloromethane, dichloroethane and chloroform; and amides,such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -50° to 30° C., more preferably from 0° to aboutroom temperature. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature, thestarting materials, the solvent employed and the nature of the reagents.However, in most cases, a period of from 10 minutes to 8 hours, morepreferably from 30 minutes to 5 hours, will normally suffice for thereaction.

After completion of this reaction, the desired compound of formula(XXIII) can be collected from the reaction mixture by conventionalmeans. For example, one suitable recovery procedure comprises: ifappropriate, neutralizing the pH; if there is a precipitate, removingthe precipitate by filtration; adding water to the residue; andextracting the mixture with a water-immiscible organic solvent, such asethyl acetate. The extract is then dried over anhydrous magnesiumsulfate, after which the solvent is removed by distillation, to give thedesired compound. If necessary, the resulting compounds can be furtherpurified by conventional means, such as recrystallization or the variouschromatography techniques, notably column chromatography.

In Step G2, a compound of formula (XXIV) is prepared by replacing theleaving group Y of the compound of formula (XXIII) with a protectedcarboxy group of formula --COOR^(5'). This reaction may be carried outby reacting the compound of formula (XXIII) with carbon monoxide and analcohol to provide the group R^(5'), in the presence of a base and apalladium catalyst (and, if necessary, a phosphine) optionally in thepresence of an additional solvent, following the procedure described in,for example, EP-0465123A, EP-0465141A or Journal of Medicinal Chemistry,33, 943 (1990).

There is no particular limitation on the palladium catalyst employed,and any palladium catalyst commonly used in reactions of this type mayequally be employed here. Examples of such catalysts includetetrakis-triphenylphosphine palladium, bistriphenylphosphine palladium(II) diacetate and palladium chloride; of these we preferbistriphenylphosphine palladium (II) diacetate.

There is no particular limitation on the phosphine employed, and anyphosphine commonly used in reactions of this type may equally beemployed here. Examples of such phosphines include triphenylphosphineand tributylphosphine; of these we prefer triphenylphosphine.

When the palladium catalyst and the phosphine are used simultaneously,they form a complex and participate in the reaction. For example, whenpalladium (II) diacetate is used as the palladium catalyst andtriphenylphosphine is used as the phosphine, they formbis(triphenylphosphine) palladium (II) diacetate and participate in thereaction.

There is no particular limitation on the nature of the base employed,and any bases commonly used in reactions of this type may equally beemployed here. Examples of such compounds include: organic amines suchas triethylamine, tripropylamine, tributylamine, diisopropylethylamine,N,N-dimethylaniline, N,N-diethylaniline, pyridine, N-methylmorpholine,2,6-di(t-butyl)-4-methylpyridine, 4-(N,N-dimethylamino) pyridine,quinoline, 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and organic metal bases, suchas butyllithium, lithium diisopropylamide and lithiumbis(trimethylsilyl)amide.

In this reaction, a quarternary ammonium salt (such asbenzyltriethylammonium chloride or tetrabutylammonium chloride) or acrown ether (such as dibenzo-18-crown-6) can be added to the reactionmixture in order to allow the reaction to proceed more effectively.

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. However, an alcohol, such as methanol, ethanol,propanol, isopropanol, butanol, isobutanol, t-butanol, isoamyl alcohol,octanol or cyclohexanol, which will be the origin of the R^(5') group isessential. Accordingly, examples of suitable solvents include: thealcohol itself and mixtures of the alcohol and one or more of thesolvents recommended for use in Step G1.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -10° to 50° C., more preferably from 0° to aboutroom temperature. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature, thestarting materials, the solvent employed and the nature of the reagents.However, in most cases, a period of from 2 to 50 hours, more preferablyfrom 3 to 30 hours, will normally suffice for the reaction.

After completion of this reaction, the desired compound of formula(XXIV) can be collected from the reaction mixture by conventional means.For example, one suitable recovery procedure comprises: if appropriate,neutralizing the pH; if there is a precipitate, removing the precipitateby filtration; adding water to the residue; and extracting the mixturewith a water-immiscible organic solvent, such as ethyl acetate. Theextract is then dried over anhydrous magnesium sulfate, after which thesolvent is removed by distillation, to give the desired compound. Ifnecessary, the resulting compounds can be further purified byconventional means, such as recrystallization or the variouschromatography techniques, notably column chromatography.

In Step G3, the compound of formula (I) is prepared by hydrolizing theprotected carboxy group of the compound of formula (XXIV) according tothe method described in Step A2, and then optionally protecting orsulfonylamidating the carboxy group thus obtained according to theprocedure described in Step A4.

Alternatively, treating the compound of formula (XXIII), obtained asdescribed in Step G1, with a base and an alkanoic acid (such as formicacid or acetic acid), and then treating it with carbon dioxide, followedby hydrolysis of the product, can yield a compound corresponding to thecompound of formula (XXIV) but which has a free carboxy group. Ifdesired, the compound of formula (I) can be prepared by protecting orsulfonylamidating the carboxy group thus obtained according to theprocedure described in Step A4.

There is no particular limitation on the nature of the base employed,and any bases commonly used in reactions for generating an anion mayequally be employed here. Examples of such bases include: organic metalbases, such as butyllithium, sec-butyllithium, t-butyllithium, lithiumdiisopropylamide and lithium bis(trimethylsilyl)amide; and organicbases, such as triethylamine, tributylamine or diisopropylamine.

The reaction is normally and preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include: aromatichydrocarbons, such as benzene, toluene and xylene; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane,diethylene glycol dimethyl ether and dioxane; halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as methylenechloride, tetrachloromethane, dichloroethane and chloroform; amides,such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulfoxides, such as dimethylsulfoxide.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -100° to 30° C., more preferably from -78° to 0° C.The time required for the reaction may likewise vary widely, dependingon many factors, notably the reaction temperature, the startingmaterials, the solvent employed and the nature of the reagents. However,in most cases, a period of from 1 to 10 hours, more preferably from 2 to8 hours, will normally suffice for the reaction.

After completion of this reaction, the desired compound of formula (I)can be collected from the reaction mixture by conventional means. Forexample, one suitable recovery procedure comprises: adding water forhydrolysis; if appropriate, neutralizing the pH; if there is aprecipitate, removing the precipitate by filtration; adding water to theresidue; and extracting the mixture with a water-immiscible organicsolvent, such as ethyl acetate. The extract is then dried over anhydrousmagnesium sulfate, after which the solvent is removed by distillation,to give the desired compound. If necessary, the resulting compounds canbe further purified by conventional means, such as recrystallization orthe various chromatography techniques, notably column chromatography.

Biological Activity

The novel steroid derivatives of the present invention have shown anexcellent ability to inhibit PG,92 testosterone 5α-reductase, combinedwith a low toxicity, and are thus useful for the prevention and therapyof prostatic hypertrophy as well as other disorders arising from excesslevels of 5=-dihydrotestosterone.

This activity is demonstrated by the following Tests, in which thecompounds of the present invention are identified by the one of thesubsequent Examples in which its preparation is illustrated. Prior artCompound B is 17β-t-butylcarbamoylandrosta-3,5-diene-3-carboxylic acid,as previously discussed.

(1) Preparation of 5β-Reductase from Rat Prostate

The ventral prostate glands of adult male rats (body weight 300 to 350g: Sprague-Dawley strain) were cut up with scissors, and about a 5-foldamount relative to the tissue of a buffer was added to the tissue. Thebuffer used was a 20 mM potassium phosphate buffer containing 0.33Msucrose, 1 mM dithiothreitol, 50 μM reduced nicotine amidoadeninedinucleotide phosphate (NADPH) and 0.001% by weight phenylmethylsulfonylfluoride (PMSF)]. The tissue was then homogenized, first with a Polytron(trade mark) homogenizer (manufactured by Kinematica, GmbH) and thenwith a Teflon-glass homogenizer (Teflon is a trade mark). The suspensionof homogenized prostate tissue was then centrifuged (140000×g, 60minutes), and the sediment was suspended by adding approximately a5-fold amount of the above buffer. The suspension was again centrifuged(140000×g, 60 minutes). The resulting sediment was used as the rat5α-reductase. This was adjusted to a protein concentration of 30 to 40mg/ml by the addition of the buffer described above, and the preparationwas then stored frozen at -80° C. Measurement of the amount of proteinwas performed using the Bio-Rad Protein Assay method, and bovineγ-globulin (Cohn Fraction II, manufactured by Sigma) was used for theprotein reference standard.

(2) Rat 5α-Reductase Inhibition Test

5 μl of a test compound was dissolved in dimethyl sulfoxide or ethanol(final concentration of test compound: 10⁻⁸ M), and the resultingsolution, 0.5 ml of a 40 mM potassium phosphate buffer (pH 6.5)containing rat 5α-reductase prepared as described above (amount ofprotein: 1 mg), 1 μM [¹⁴ C]-testosterone, 1 mM dithiothreitol and 500 μMNADPH were placed in a test tube. The mixture was then incubated at 37°C. for 15 to 30 minutes. Testing was also performed on a control groupby adding solvent only. Following incubation, 2 ml of ethyl acetate,containing 10 μg each of testosterone, 5α-dihydrotestosterone andandrostenedione, were added to stop the reaction. The reaction mixturewas centrifuged (1400×g, 5 minutes), and then the ethyl acetate fractionwas transferred to a separate test tube and evaporated to dryness in thepresence of circulating nitrogen gas. The steroid was dissolved in 40 μlof ethyl acetate and spotted onto a thin layer chromatographic plate(LK5DF silica plate, manufactured by Whatman). The plate was thendeveloped twice at room temperature with a mixture of ethyl acetate andcyclohexane (1:1 by volume). The steroid fraction was identified withultraviolet light and stained using an aqueous solution of 1% w/v cesiumsulfate and 10% w/v sulfuric acid. The radioactivity profiles of thethin layer chromatographic plate were measured using a bio-imageanalyzer (manufactured by Fuji Photo Film). Enzyme activity wasexpressed as the proportion of [¹⁴ C]-5α-dihydrotestosterone that wasconverted from the [¹⁴ C]-testosterone (conversion rate (%)) added. Inaddition, the rat 5α-reductase inhibitory activity of the specimen wasdetermined using the following formula.

    Rat 5α-Reductase Inhibitory Activity=(conversion rate of test group)/(conversion rate of control group)×100 (%)

The results are shown in the following Table 2.

                  TABLE 2                                                         ______________________________________                                                  Inhibitory Activity                                                                       ID.sub.50                                               ______________________________________                                        Compound                                                                      of Ex. No.                                                                    1           70.6          --                                                  2           70.6          3.6 × 10.sup.-9                               6           89.4          --                                                  7           70.3          4.2 × 10.sup.-9                               9           77.9          4.3 × 10.sup.-9                               11          73.5          --                                                  12          74.0          --                                                  13          84.3          --                                                  15          73.3          4.96 × 10.sup.-9                              16          81.7          --                                                  21          84.9          --                                                  25          79.3          --                                                  Compound B  28.1          3.37 × 10.sup.-8                              ______________________________________                                    

As can be seen from the above results, the compounds of the presentinvention have excellent inhibitory activity against the action of5α-reductase, which is an order of magnitude higher than the closestprior art compound, which itself is under investigation for humantherapeutic use.

The compounds of the present invention may be administered by anysuitable route and may be formulated, as is well known in the art, inpharmaceutical compositions with conventional adjuvants, carriers,diluents or other active compounds, depending upon the nature of thedisorder to be treated and the route of administration. For example, fororal administration the compounds may be formulated as tablets,capsules, granules, powders and syrups; and for parenteraladministration they may be formulated as injections and suppositories.These pharmaceutical preparations can be prepared by conventional meansusing such additives as vehicles, binders, disintegrators, lubricants,stabilizers and corrigents. Although the dosage may be vary dependingupon symptoms, body weight and age of the patients, as well as thenature and severity of the disorder to be treated or prevented, theusual daily dosage for an adult is from 0.01 to 1000 mg, preferably from0.1 to 100 mg, which may be administered as a single dose or in divideddoses, several times a day.

The invention is further illustrated by the following Examples, whichillustrate the preparation of certain of the compounds of the presentinvention, and by the subsequent Preparations, which illustrate thepreparation of certain of the starting materials used in these Examples.

EXAMPLE 1

17β-[N-(Diphenylmethyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid(Compound No. 2)

1(a) Methyl 3-cyanoandrosta-3,5-diene-17β-carboxylate

3.0 g of lithium cyanide and 16 ml of diethyl cyanophosphate weredissolved in 200 ml of dry tetrahydrofuran, and 10 g of methyl3-oxo-4-androstene-17β-carboxylate were added little by little at roomtemperature to the resulting solution. The reaction mixture was stirredat room temperature for 15 minutes, after which the tetrahydrofuran wasremoved by distillation under reduced pressure. The residue wasdissolved in 300 ml of a 1:1 by volume mixture of ethyl acetate andbenzene, and the resulting solution was washed four times with water andthen once with a saturated aqueous solution of sodium chloride. It wasthen dried over anhydrous magnesium sulfate, and concentrated byevaporation under reduced pressure. The resulting residue was dissolvedin 100 ml of dry benzene, and 2 ml of a boron trifluoride-diethyl ethercomplex was added to the resulting solution, which was then stirred atroom temperature for 3 hours. At the end of this time, the reactionmixture was diluted with 300 ml of diethyl ether. The diluted mixturewas washed with water, with an aqueous solution of sodiumhydrogencarbonate and with a saturated aqueous solution of sodiumchloride, in that order, after which it was dried over anhydrousmagnesium sulfate, and then concentrated by evaporation under reducedpressure. The resulting residue was subjected to column chromatographythrough 100 g of silica gel using a gradient elution method, withmixtures of ethyl acetate and hexane in ratios ranging from 4:96 to12:88 by volume as the eluent, to give 9.5 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.70 (3H, singlet);0.93 (3H, singlet); 0.90-2.50 (18H, multiplet); 3.67 (3H, singlet); 5.77(1H, triplet, J=3 Hz); 6.65 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2940, 2885, 2205,1729, 1635, 1603, 1436, 1200, 1161, 1058, 935, 652, 541.

1(b) 3-Cyanoandrosta-3,5-diene-17β-carboxylic acid

8.8 g of methyl 3-cyanoandrosta-3,5-diene-17β-carboxylate [prepared asdescribed in step (a) above] and 4.3 g of potassium hydroxide weredissolved in a mixture of 20 ml of water and 200 ml of methanol, and theresulting solution was heated under reflux for 10 hours. At the end ofthis time, the methanol in the reaction mixture was removed bydistillation under reduced pressure, the mixture was made acidic by theaddition of dilute aqueous hydrochloric acid and extracted three timeswith methylene chloride. The organic extract was washed with water andthen with a saturated aqueous solution of sodium chloride and dried overanhydrous magnesium sulfate. It was then concentrated by evaporationunder reduced pressure. The resulting residue was subjected to columnchromatography through 150 g of silica gel using a gradient elutionmethod, with mixtures of acetone and methylene chloride in ratiosranging from 2:98 to 16:84 by volume as the eluent, to give 7.1 g of thetitle compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.78 (3H, singlet);0.94 (3H, singlet); 0.90-2.50 (18H, multiplet); 5.77 (1H, triplet, J=3Hz); 6.65 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2968, 2944, 2855,2205, 1698, 1634, 1603, 1421, 1296, 1238, 932, 730, 650.

1(c) N-(Diphenylmethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

1.0 g of 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared asdescribed in step (b) above], 1.0 ml of diphenylmethylamine and 1.0 mlof triethylamine were dissolved in 10 ml of dry methylene chloride, and0.75 ml of diethyl cyanophosphate was added to the resulting solution atroom temperature. The reaction mixture was stirred at room temperatureovernight, after which it was diluted with 100 ml of methylene chloride,and then washed with 1N aqueous hydrochloric acid, with water, with anaqueous solution of sodium hydrogencarbonate and with a saturatedaqueous solution of sodium chloride, in that order. The solution wasthen dried over anhydrous magnesium sulfate, after which it wasconcentrated by evaporation under reduced pressure. The resultingresidue was subjected to column chromatography through 40 g of silicagel using a gradient elution method, with mixtures of acetone andmethylene chloride in ratios ranging from 1:99 to 4:96 by volume as theeluent, to give 0.85 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.70 (3H, singlet);0.92 (3H, singlet); 0.90-2.00 (13H, multiplet); 2.18-2.36 (5H,multiplet); 5.76 (1H, triplet, J=2 Hz); 5.88 (1H, doublet, J=8 Hz); 6.29(1H, doublet, J=8 Hz); 6.64 (1H, singlet); 7.21-7.36 (10H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2967, 2950, 2912,2205, 1664, 1636, 1603, 1485, 1449, 1199, 757, 697.

1(d) 17β-[N-(Diphenylmethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid

0.8 g of N-diphenylmethyl-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (c) above] and 6.0 g of potassiumhydroxide were dissolved in a mixture of 14 ml of water and 20 ml ofethylene glycol, and then the mixture was heated under reflux for 16hours. At the end of this time, the reaction mixture was cooled to roomtemperature and made acidic by the addition of dilute aqueoushydrochloric acid. The mixture was then extracted three times withmethylene chloride. The combined organic extracts were washed with waterand with a saturated aqueous solution of sodium chloride, in that orderand dried over anhydrous magnesium sulfate. The mixture was thenconcentrated by evaporation under reduced pressure. The resultingresidue was subjected to column chromatography through 35 g of silicagel using a gradient elution method, with mixtures of acetone andmethylene chloride in ratios ranging from 2:98 to 12:88 by volume as theeluent, to give 650 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.91 (3H, singlet); 0.90-2.60 (18H, multiplet); 5.86 (1H, triplet, J=3Hz); 5.89 (1H, doublet, J=8 Hz); 6.30 (1H, doublet, J=8 Hz); 7.13 (1H,singlet); 7.20-7.40 (10H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3337, 2942, 1710,1698, 1674, 1634, 1530, 1496, 1367, 1230, 1203, 1170, 755, 700, 641.

EXAMPLE 2

17β-{N-[1-(4-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 142)

2(a) S-2-Pyridyl 3-oxo-4-androstene-17β-thiocarboxylate

10.0 g of 3-oxo-4-androstene-17β-carboxylic acid, 14.0 g of 2,2'-pyridyldisulfide and 16.7 g of triphenylphosphine were dissolved in 100 ml ofdry toluene, and the resulting solution was stirred at room temperaturefor 24 hours in a stream of nitrogen. At the end of this time, thereaction mixture was subjected, without further treatment, to silica gelcolumn chromatography, using a 1:1 by volume mixture of hexane and ethylacetate as the eluent, to give 12.0 g of the title compound as whitecrystals.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.80 (3H, singlet);0.95-2.12 (13H, multiplet); 1.19 (3H, singlet); 2.20-2.49 (6H,multiplet); 2.74 (1H, triplet, J=9.3 Hz); 5.74 (1H, singlet); 7.27-7.31(1H, multiplet); 7.59-7.63 (1H, multiplet); 7.70-7.77 (1H, multiplet);8.61-8.64 (1H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2967, 2936, 1691,1664, 1568, 1563, 1418.

2(b)N-[1-(4-Methoxyphenyl)-1-methylethyl]-3-oxo-4-androstene-17β-carboxamide

610 mg of S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [preparedas described in step (a) above] were dissolved in 1 ml of dry methylenechloride, and 630 mg of 1-(4-methoxyphenyl)-1-methylethylamine (preparedas described in Preparation 10a) were added to the resulting solution.The mixture was then stirred at room temperature for 3 days. At the endof this time, the reaction mixture was subjected, without furthertreatment, to silica gel column chromatography using a gradient elutionmethod, with mixtures of methylene chloride and acetone in ratiosranging from 3:2 to 1:1 by volume as the eluent, and the product wasrecrystallized from diisopropyl ether, to give 670 mg of the titlecompound as white crystals.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.91-1.90 (12H, multiplet); 1.19 (3H, singlet); 1.70 (3H, singlet); 1.71(3H, singlet); 1.99-2.46 (8H, multiplet); 3.79 (3H, singlet); 5.47 (1H,singlet); 5.73 (1H, singlet); 6.86 (2H, doublet, J=8.8 Hz); 7.33 (2H,doublet, J=8.8 Hz).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3353, 2966, 2941,1661, 1614, 1513, 1454.

2(c)N-[1-(4-Methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

660 mg ofN-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-androstene-17β-carboxamide[prepared as described in step (b) above] were dissolved in 5 ml of drytetrahydrofuran, and 0.30 ml of diethyl cyanophosphate and 67 mg oflithium cyanide were added to the resulting solution. The mixture wasthen stirred at room temperature for 30 minutes. At the end of thistime, the solvent was removed from the reaction mixture by distillationunder reduced pressure, and the resulting residue was dissolved in a 1:1by volume mixture of ethyl acetate and benzene. The resulting solutionwas then washed with water and with a saturated aqueous solution ofsodium chloride, in that order; it was then dried over anhydrous sodiumsulfate. The solvent was then removed by distillation under reducedpressure. The resulting residue was dissolved in 5 ml of dry toluene,and the solution thus obtained was stirred at room temperature for 4hours, whilst a boron trifluoride - diethyl ether complex was added inan amount of 20 μl every 30 minutes. At the end of this time, asaturated aqueous solution of sodium hydrogencarbonate was added to thereaction mixture, and the resulting mixture was extracted with a 1:1 byvolume mixture of ethyl acetate and benzene. The extract was washed withwater and with a saturated aqueous solution of sodium chloride, in thatorder, and dried over anhydrous sodium sulfate. The solvent was thenremoved from the mixture by evaporation under reduced pressure. Theresidue was subjected to silica gel column chromatography using agradient elution method, with mixtures of hexane and ethyl acetate inratios ranging from 3:1 to 3:2 by volume as the eluent, and the productwas crystallized from diisopropyl ether, to give 300 mg of the titlecompound as white crystals.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.70 (3H, singlet);0.93 (3H, singlet); 0.97-1.92 (10H, multiplet); 1.70 (3H, singlet); 1.71(3H, singlet); 1.99-2.38 (8H, multiplet); 3.79 (3H, singlet); 5.49 (1H,singlet); 5.77 (1H, triplet, J=3.2 Hz); 6.65 (1H, singlet); 6.86 (2H,doublet, J=8.8 Hz); 7.34 (2H, doublet, J=8.8 Hz).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3399, 2962, 2914,2199, 1681, 1632, 1615, 1598, 1512, 1455.

2(d)17β-{N-[1-(4-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid

280 mg ofN-[1-(4-methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (c) above] were suspended in 15 ml ofethylene glycol, and a solution of 2.2 g of potassium hydroxide in 5 mlof water was added to the resulting suspension. The mixture was thenheated under reflux for 24 hours in a nitrogen stream. At the end ofthis time, the reaction mixture was cooled to room temperature and madeacidic by the addition of 10% w/v aqueous hydrochloric acid, and thenthe mixture was extracted with methylene chloride. The extract waswashed with water and with a saturated aqueous solution of sodiumchloride, in that order, after which it was dried over anhydrous sodiumsulfate. The solvent was then removed from the mixture by evaporationunder reduced pressure. The residue was recrystallized from a mixture ofacetone and diethyl ether, and the resulting crystals were collected byfiltration. The mother liquor was purified by silica gel columnchromatography using a gradient elution method, with mixtures ofmethylene chloride and acetone in ratios ranging from 9:1 to 7:3 byvolume as the eluent, to give 268 mg of the title compound as whitepowdery crystals.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.93 (3H, singlet); 1.03-2.60 (18H, multiplet); 1.70 (3H, singlet); 1.72(3H, singlet); 3.80 (3H, singlet); 5.51 (1H, singlet); 5.85 (1H,triplet, J=2.7 Hz); 6.86 (2H, doublet, J=8.8 Hz); 7.12 (1H, singlet);7.34 (2H, doublet, J=8.8 Hz).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3448, 2966, 2940,1663, 1633, 1612, 1514, 1420.

EXAMPLE 3

17β-[N-(Diphenylamino)carbamoyl]androsta-3,5-diene-3-carboxylic acid(Compound No. 159)

3(a) S-2-Pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate

7.0 g of 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared asdescribed in Example l(b)], 10.2 g of triphenylphosphine and 8.8 g of2,2'-dipyridyl disulfide were dissolved in 100 ml of dry benzene, andthe resulting solution was stirred at room temperature overnight. At theend of this time, the reaction mixture was subjected, without furthertreatment, to column chromatography through 350 g of silica gel using agradient elution method, with mixtures of acetone and methylene chloridein ratios ranging from 1:99 to 2:98 by volume as the eluent, to give 6.9g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.79 (3H, singlet);0.94 (3H, singlet); 0.80-2.50 (17H, multiplet); 2.74 (1H, triplet, J=9Hz); 5.77 (1H, triplet, J=2 Hz); 6.65 (1H, singlet); 7.25-7.31 (1H,multiplet); 7.60-7.64 (1H, multiplet); 7.71-7.78 (1H, multiplet);8.61-8.64 (1H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2957, 2946, 2911,2200, 1708, 1631, 1573, 1454, 1420, 1152, 1039, 768.

3(b) N,N-Diphenyl-3-cyanoandrosta-3,5-diene-17β-carbohydrazide

505 mg of S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in step (a) above] were dissolved in 7 ml ofpyridine, and 330 mg of 1,1-diphenylhydrazine hydrochloride were addedto the resulting solution. The mixture was then stirred at roomtemperature overnight. At the end of this time, the solvent was removedfrom the reaction mixture by distillation under reduced pressure, andthe residue was subjected to silica gel column chromatography using agradient elution method, with mixtures of methylene chloride and acetonein ratios ranging from 99:3 to 9:1 by volume as the eluent, and theproduct was crystallized from diisopropyl ether, to give 500 mg of thetitle compound as white crystals.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.74 (3H, singlet);0.94 (3H, singlet); 1.03-1.95 (12H, multiplet); 2.04-2.38 (6H,multiplet); 5.77 (1H, triplet, J=2.9 Hz); 6.65 (1H, singlet); 6.98-7.33(10H, multiplet); 7.43 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3230, 2943, 2909,2208, 1667, 1634, 1591, 1496.

3(c) 17β-[N-(Diphenylamino)carbamoyl]androsta-3,5-diene-3-carboxylicacid

A procedure similar to that described in Example 1(d) was repeated,except that N,N-diphenyl-3-cyanoandrosta-3,5-diene-17β-carbohydrazide[prepared as described in step (b) above] was employed as a startingmaterial, in a relative amount similar to that used in that Example, togive the title compound in a yield of 80%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.74 (3H, singlet);0.93 (3H, singlet); 1.02-2.58 (18H, multiplet); 5.86 (1H, triplet, J=2.7Hz); 6.98-7.36 (11H, multiplet ); 7.44 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3265, 2940, 1677,1633, 1591, 1495.

EXAMPLE 4

17β-[N-(1-Methyl-1-phenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 66)

4(a)N-(1-Methyl-1-phenylethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

A procedure similar to that described in Example 3(b) was repeated,except that S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and 1-methyl-1-phenylethylaminewere used as starting materials, in relative proportions similar tothose used in that Example, to give the title compound in a yield of75%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.94 (3H, singlet); 0.98-1.92 (12H, multiplet); 1.71 (3H, singlet); 1.73(3H, singlet); 2.02-2.40 (6H, multiplet); 5.53 (1H, singlet); 5.77 (1H,triplet, J=3.4 Hz); 6.65 (1H, singlet); 7.19-7.44 (5H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3445, 2964, 2896,2861, 2202, 1685, 1640, 1603, 1495.

4(b)17β-[N-(1-Methyl-1-phenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid

A procedure similar to that described in Example 1(d) was repeated,except thatN-(1-methyl-1-phenylethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] was employed as a startingmaterial, in a relative amount similar to that used in that Example, togive the title compound in a yield of 82%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.72 (3H, singlet);0.93 (3H, singlet); 1.01-2.57 (18H, multiplet); 1.71 (3H, singlet); 1.74(3H, singlet); 5.54 (1H, singlet); 5.87 (1H, broad singlet); 7.14 (1H,singlet); 7.20-7.44 (5H, multiplet).

Infrared Absorption Spectrum (KBr), νmax cm⁻¹ : 3440, 2940, 1680, 1667,1632, 1608, 1495.

EXAMPLE 5

17β-{N-[1-Methyl-1-(3-thienyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 191)

Procedures similar to those described in Examples 4(a) and 4(b) wererepeated, except that S-2-pyridyl3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described inExample 3 (a)] and 1-methyl-1-(3-thienyl) ethylamine (prepared asdescribed in Preparation 11b) were employed as starting materials, inrelative proportions similar to those used in that Example, to give thetitle compound in a yield of 55%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.93 (3H, singlet); 1.70 (3H, singlet); 1.73 (3H, singlet); 5.53 (1H,singlet); 5.85 (1H, broad singlet); 6.9-7.0 (2H, multiplet); 7.14 (1H,singlet); 7.28 (1H, multiplet).

EXAMPLE 6

17β-[N-(1,2-Diphenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid(Compound No. 1)

6(a) N-(1,2-Diphenylethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

A procedure similar to that described in Example 3(b) was repeated,except that S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and 1,2-diphenylethylamine wereemployed as starting materials, in relative proportions similar to thoseused in that Example, to give the title compound in a quantitativeyield.

Infrared Absorption Spectrum (KBr), ν_(max) cm³¹ 1 : 3416, 2965, 2948,2913, 2204, 1658, 1636, 1603, 1495, 1454, 1234, 699.

6(b) 17β-[N-(1,2-Diphenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusing 630 mg ofN-(1,2-diphenylethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above], the title compound wasobtained in a yield of 41%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.50 & 0.54(together 3H, each singlet); 0.88 & 0.90 (together 3H, each singlet);0.93-2.55 (18H, multiplet); 2.99-3.21 (2H, multiplet); 5.24-5.39 (1H,multiplet); 5.50 & 5.60 (together 1H, each doublet, J=7.0 Hz); 5.84 (1H,singlet); 7.04-7.35 (11H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3029, 2940, 1671,1633, 1610, 1496, 1278, 1188, 698.

EXAMPLE 7

17β-{N-[1-(3,4-Dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 192)

7(a)N-[1-(3,4-Dimethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(3,4-dimethoxyphenyl)-1-methylethylamine (prepared as described inPreparation 10e) as starting materials, in relative proportions similarto those used in that Example, the title compound was obtained in ayield of 60%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻ : 3374, 2965, 2938,2203, 1676, 1634, 1604, 1518, 1453, 1261, 1145, 1029.

7(b)17β-{N-[1-(3,4-Dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(3,4-dimethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 58%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.72 (3H, singlet);0.92 (3H, singlet); 1.03-2.57 (18H, multiplet); 1.71 (3H, singlet); 1.72(3H, singlet); 3.86 (3H, singlet); 3.88 (3H singlet); 5.51 (1H,singlet); 5.86 (1H, singlet); 6.81-6.84 (1H, multiplet); 6.95-6.99 (2H,multiplet); 7.14 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3437, 2967, 2939,1674, 1633, 1610, 1518, 1453, 1262, 1145, 1028, 803, 766, 641.

EXAMPLE 8

17β-{N-[1-(2-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 168)

8(a)N-[1-(2-Methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(2-methoxyphenyl)-1-methylethylamine (prepared as described inPreparation 10c) as starting materials, in relative proportions similarto those used in that Example, the title compound was obtained in ayield of 96%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3386, 2939, 2203,1675, 1633, 1602, 1490, 1451, 1380, 1241, 1029, 752.

8(b)17β-{N-[1-(2-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(2-methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 50%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.67 (3H, singlet);0.91 (3H, singlet); 1.00-2.56 (18H, multiplet); 1.77 (3H, singlet); 1.81(3H, singlet); 3.83 (3H, singlet); 5.86 (1H, singlet); 5.97 (1H,singlet); 6.87-6.97 (2H, multiplet); 7.14 (1H, singlet); 7.19-7.26 (1H,multiplet); 7.38-7.42 (1H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3450, 2972, 2939,1670, 1634, 1607, 1490, 1452, 1288, 1241, 1189, 1019, 754, 641.

EXAMPLE 9

17β-{N-[1-(3-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 166)

9(a)N-[1-(3-Methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(3-methoxyphenyl)-1-methylethylamine (prepared as described inPreparation 10b) as starting materials, in relative proportions similarto those used in that Example, the title compound was obtained in ayield of 64%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3347, 2966, 2940,2203, 1675, 1633, 1603, 1584, 1486, 1448, 1266, 1049, 700.

9(b)17β-{N-[1-(3-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(3-methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 33%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.73 (3H, singlet);0.93 (3H, singlet); 1.04-2.57 (18H, multiplet); 1.70 (3H, singlet); 1.72(3H, singlet); 3.80 (3H, singlet); 5.54 (1H, singlet); 5.85 (1H,singlet); 6.75-6.79 (1H, multiplet); 6.95-7.02 (2H, multiplet); 7.14(1H, singlet); 7.23-7.29 (1H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3438, 2966, 2939,1666, 1632, 1608, 1583, 1498, 1454, 1428, 1275, 1233, 1188, 1049, 780,701.

EXAMPLE 10

17β-{N-[1-(3,5-Dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 149)

10(a)N-[1-(3,5-Dimethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(3,5-dimethoxyphenyl)-1-methylethylamine (prepared as described inPreparation 10d) as starting materials, in relative proportions similarto those used in that Example, the title compound was obtained in ayield of 83%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3358, 2965, 2940,2202, 1679, 1633, 1598, 1504, 1453, 1421, 1204, 1153, 1052, 696.

10(b)17β-{N-[1-(3,5-Dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(3,5-dimethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 51%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.74 (3H, singlet);0.93 (3H, singlet); 1.04-2.63 (18H, multiplet); 1.68 (3H, singlet); 1.71(3H, singlet); 3.79 (6H, singlet); 5.53 (1H, singlet); 5.85 (1H,singlet); 6.34 (1H, triplet, J=2.0 Hz); 6.56 (2H, doublet, J=2.0 Hz);7.13 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3344, 2965, 2939,1676, 1634, 1598, 1503, 1456, 1423, 1292, 1204, 1154, 1066, 834, 696,640.

EXAMPLE 11

17β-{N-[1-(4-Methylphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 196)

11(a)N-[1-(4-Methylphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(4-methylphenyl)-1-methylethylamine (prepared as described inPreparation 10h) as starting materials, in relative proportions similarto those used in that Example, the title compound was obtained in ayield of 88%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3446, 2963, 2896,2203, 1685, 1637, 1604, 1495, 1382, 1257, 810, 541.

11(b)17β-{N-[1-(4-Methylphenyl)-1-methylethyl]-carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(4-methylphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 47%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.72 (3H, singlet);0.92 (3H, singlet); 0.99-2.56 (18H, multiplet); 1.70 (3H, singlet); 1.72(3H, singlet); 2.32 (3H, singlet); 5.52 (1H, singlet); 5.86 (1H,singlet); 7.14 (2H, doublet, J=7.8 Hz); 7.15 (1H, singlet); 7.28 (2H,doublet, J=7.8 Hz).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3437, 2968, 2940,1666, 1633, 1610, 1494, 1452, 1420, 1277, 1188, 815, 640, 552.

EXAMPLE 12

17β-[N-(1-Ethyl-1-phenylpropyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 195)

12(a) N-(1-Ethyl-1-phenylpropyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and 1-ethyl-1-phenylpropylamineas starting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 79%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3358, 2965, 2937,2203, 1678, 1634, 1603, 1510, 1495, 1446, 1380, 1235, 757, 698.

12(b)17β-[N-(1-Ethyl-1-phenylpropyl)carbamoyl]-androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-(1-ethyl-1-phenylpropyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 37%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.72 (6H, triplet,J=7.6 Hz); 0.77 (3H, singlet); 0.93 (3H, singlet); 1.03-2.57 (22H,multiplet); 5.42 (1H, singlet); 5.88 (1H, singlet); 7.14 (1H, singlet);7.19-7.37 (5H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3441, 2968, 2939,1675, 1633, 1608, 1495, 1446, 1421, 1378, 1279, 1188, 757, 698, 640.

EXAMPLE 13

17β-{N-[1-(4-Ethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No.194)

13(a)N-[1-(4-Ethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(4-ethoxyphenyl)-1-methylethylamine (prepared as described inPreparation 10g) as starting materials, in relative proportions similarto those used in that Example, the title compound was obtained in ayield of 91%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3361, 2969, 2940,2203, 1678, 1633, 1609, 1512, 1453, 1243, 1181, 1048, 833.

13(b)17β-{N-[1-(4-Ethoxyphenyl)-1-methylethyl]-carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(4-ethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 50%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.92 (3H, singlet); 1.05-2.50 (18H, multiplet); 1.40 (3H, triplet, J=6.8Hz); 1.70 (3H, singlet); 1.72 (3H, singlet); 4.00 (2H, quartet, J=6.8Hz); 5.49 (1H, singlet); 5.86 (1H, singlet); 6.84 (2H, doublet, J=7.0Hz); 7.14 (1H, singlet); 7.32 (2H, doublet, J=7.0 Hz).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2968, 2938, 1682,1631, 1609, 1512, 1280, 1244, 1183, 1047, 926, 824, 639.

EXAMPLE 14

17β-{N-[1-Methyl-1-(2-thienyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 67)

14(a) N-[1-Methyl-1-(2-thienyl)ethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-methyl-1-(2-thienyl)ethylamine (prepared as described in Preparation11a) as starting materials, in relative proportions similar to thoseused in that Example, the title compound was obtained in a yield of 88%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3350, 2966, 2941,2203, 1679, 1634, 1603, 1500, 1452, 1382, 1246, 695.

14(b) 17β-{N-[1-Methyl-1-(2-thienyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylic acid

Following a procedure similar to that described in Example 1(d), butusingN-[1-methyl-1-(2-thienyl)ethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 57%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.72 (3H, singlet);0.92 (3H, singlet); 0.95-2.57 (18H, multiplet); 1.82 (3H, singlet); 1.83(3H, singlet); 5.54 (1H, singlet); 5.85 (1H, singlet); 6.95 (1H, doubletof doublets, J=5.0 & 3.0 Hz); 7.10 (1H, doublet of doublets, J=3.0 & 1.0Hz); 7.15 (1H, singlet); 7.19 (1H, doublet of doublets, J=5.0 & 1.0 Hz).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3400, 2967, 2940,1673, 1633, 1609, 1490, 1419, 1279, 1188, 704.

EXAMPLE 15

17β-[N-(4-Hydroxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 127)

15(a) N-(4-Hydroxybenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and 4-hydroxybenzhydrylamine(prepared as described in Preparation 13) as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 83%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3327, 2966, 2942,2910, 2204, 1640, 1614, 1601, 1514, 1495, 1232, 1171, 699.

15(b) 17β-[N-(4-Hydroxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylic acid

Following a procedure similar to that described in Example 1(d), butusing N-(4-hydroxybenzhydryl)-3-cyanoandrosta- 3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 34%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.91 (3H, singlet); 1.06-2.64 (19H, multiplet); 5.87 (1H, singlet); 5.87& 5.97 (together 1H, each doublet, J=7.0 Hz); 6.72-6.76 (2H, multiplet);7.03-7.37 (8H, multiplet).

Infrared Absorption Spectrum (KBr), νmax cm⁻¹ : 3310, 2966, 2940, 1675,1636, 1614, 1514, 1495, 1271, 1232, 1186, 1172, 699.

EXAMPLE 16

17β-[N-(4,4'-Difluorobenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 12)

16(a)N-(4,4'-Difluorobenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and 4,4'-difluorobenzhydrylamine(prepared as described in Preparation 12) as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 91%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3346, 2967, 2948,2912, 2205, 1661, 1636, 1604, 1508, 1488, 1229, 1158, 833, 552.

16(b) 17β-[N-(4,4'-Difluorobenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylic acid

Following a procedure similar to that described in Example 1(d), butusing [-(4,4'-difluorobenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide [preparedas described in step (a) above] as a starting material, in a relativeamount similar to that used in that Example, the title compound wasobtained in a yield of 34%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.70 (3H, singlet);0.92 (3H, singlet); 0.96-2.56 (18H, multiplet); 5.78 (1H, doublet, J=7.8Hz); 5.86 (1H, singlet); 6.25 (1H, doublet, J=7.8 Hz); 7.08 (4H,multiplet); 7.13-7.23 (5H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2942, 2910, 1669,1634, 1607, 1508, 1419, 1279, 1228, 1189, 1158, 833, 552.

EXAMPLE 17

17β-[N-(4,4'-Dimethoxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 14)

17(a)N-(4,4'-Dimethoxybenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamid

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and4,4'-dimethoxybenzhydrylamine (prepared as described in Preparation 14)as starting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 79%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3425, 2945, 2908,2205, 1657, 1637, 1607, 1511, 1488, 1248, 1176, 1036, 835, 567.

17(b)17β-[N-(4,4'-Dimethoxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-(4,4'-dimethoxybenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 52%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.91 (3H, singlet); 1.02-2.49 (18H, multiplet ); 3.79 (6H, singlet);5.81 (1H, doublet, J=7.8 Hz); 5.86 (1H, singlet); 6.19 (1H, doublet,J=7.8 Hz); 6.82-6.89 (4H, multiplet); 7.12-7.17 (5H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2940, 2910, 1666,1635, 1610, 1511, 1248, 1175, 1035, 829, 640, 565.

EXAMPLE 18

17β-{N-[1-(4-N,N-Dimethylaminophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 190)

18(a)N-[1-(4-N,N-Dimethylaminophenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(4-N,N-dimethylaminophenyl)-1-methylethylamine (prepared as describedin Preparation 10i) as starting materials, in relative proportionssimilar to those used in that Example, the title compound was obtainedin a yield of 83%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3351, 2965, 2939,2202, 1677, 1632, 1614, 1522, 1493, 1446, 1359, 1200, 815.

18(b)17β-{N-[1-(4-N,N-Dimethylaminophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(4-N,N-dimethylaminophenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 35%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.73 (3H, singlet);0.93 (3H, singlet); 0.99-2.57 (18H, multiplet); 1.71 (3H, singlet); 1.73(3H, singlet); 2.95 (6H, singlet); 5.48 (1H, singlet); 5.86 (1H,singlet); 6.65-6.85 (2H, broad singlet); 7.14 (1H, singlet); 7.25-7.37(2H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2967, 2939, 2915,1680, 1664, 1631, 1613, 1522, 1498, 1420, 1359, 1276, 949, 817, 640.

EXAMPLE 19

17β-{N-[1-(4-Fluorophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 78)

19(a)N-[1-(4-Fluorophenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1-(4-fluorophenyl)-1-methylethylamine (prepared as described inPreparation 10f) as starting materials, in relative proportions similarto those used in that Example, the title compound was obtained in ayield of 82%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3439, 2966, 2946,2204, 1673, 1634, 1601, 1512, 1494, 1232, 1164, 836.

19(b)17β-{N-[1-(4-Fluorophenyl)-1-methylethyl]-carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[1-(4-fluorophenyl)-1-methylethyl]-3-cyanoandrosta-3,5diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 55%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.69 (3H, singlet);0.93 (3H, singlet); 1.00-2.57 (18H, multiplet); 1.68 (3H, singlet); 1.70(3H, singlet); 5.53 (1H, singlet); 5.86 (1H, singlet); 7.00 (2H,triplet, J=8.8 Hz); 7.13 (1H, singlet); 7.37 (2H, doublet of doublets,J=8.8 & 5.4 Hz).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3440, 2966, 2939,1675, 1633, 1609, 1510, 1420, 1276, 1231, 832, 551.

EXAMPLE 20

17β-[N-(4-Chlorobenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 27)

20(a) N-(4-Chlorobenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5 -diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and 4-chlorobenzhydrylamine asstarting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 70%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3349, 2965, 2945,2205, 1661, 1637, 1603, 1490, 1453, 1090, 1014, 754.

20(b)17β-[N-(4-Chlorobenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusing N-(4-chlorobenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 38%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.70 (3H, singlet);0.91 & 0.92 (together 3H, each singlet); 1.00-2.56 (18H, multiplet);5.82-5.87 (2H, multiplet); 6.25 & 6.26 (together 1H, each doublet, J=7.8Hz); 7.13-7.38 (10H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2941, 2910, 1674,1635, 1613, 1490, 1279, 1209, 1188, 1090, 1014, 700.

EXAMPLE 21

17β-[N-(4-Methoxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 28)

21(a) N-(4-Methoxybenzhydryl)-3-cyanoandrosta-3,5-diene -17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and 4-methoxybenzhydrylamine(prepared as described in Preparation 15) as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 82%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻ : 3344, 2964, 2945,2910, 2205, 1661, 1636, 1607, 1511, 1493, 1249, 1177, 1033, 700.

21(b)17β-[N-(4-Methoxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusing N-(4-methoxybenzhydryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 37%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.91 (3H, singlet); 1.00-2.56 (18H, multiplet); 3.79 & 3.80 (together3H, each singlet); 5.85 (1H, doublet, J=7.8 Hz); 5.86 (1H, singlet);6.24 (1H, doublet, J=7.8 Hz); 6.84-6.90 (2H, multiplet); 7.10-7.37 (8H,multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2939, 2910, 1672,1635, 1612, 1511, 1495, 1454, 1248, 1177, 1033, 699, 640.

EXAMPLE 22

17β-[N-(1,1-Dimethyl-2-phenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 76)

22(a)N-(1,1-Dimethyl-2-phenylethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and1,1-dimethyl-2-phenylethylamine as starting materials, in relativeproportions similar to those used in that Example, the title compoundwas obtained in a yield of 82%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3436, 2965, 2938,2916, 2205, 1678, 1633, 1604, 1501, 1451, 1385, 1233, 922, 729, 705.

22 (b)17β-[N-(1,1-Dimethyl-2-phenylethyl)carbamoyl]-androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-(1,1-dimethyl-2-phenylethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 45%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.73 (3H, singlet);0.91 (3H, singlet); 0.96-2.56 (18H, multiplet); 1.27 (3H, singlet); 1.44(3H, singlet); 2.82 (1H, doublet, J=13.2 Hz); 3.21 (1H, doublet, J=13.2Hz); 4.99 (1H, singlet); 5.85 (1H, singlet); 7.14 (1H, singlet);7.16-7.32 (5H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2963, 2939, 2913,1681, 1661, 1633, 1610, 1502, 1419, 1276, 1189, 924, 701.

EXAMPLE 23

17β-[N-(α,α-Dimethylfurfuryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid (Compound No. 178)

23(a) N-(α,α-Dimethylfurfuryl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and α,α-dimethylfurfurylamine(prepared as described in Preparation 11c) as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 71%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2968, 2945, 2911,2201, 1707, 1631, 1603, 1573, 1449, 1420, 1038, 767.

23(b) 17β-N-(α,α-Dimethylfurfuryl)carbamoyl]androsta-35-diene-3-carboxylic acid

Following a procedure similar to that described in Example f1(d), butusingN-(α,α-dimethylfurfuryl)carbamoyl]cyanoandrosta-3,5-diene-17.beta.-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 27%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.67 (3H, singlet);0.92 (3H, singlet); 0.99-2.57 (18H, multiplet); 1.70 (3H, singlet) 1.72(3H, singlet) 5.52 (1H, singlet) 5.86 (1H, singlet) 6.19-6.21 (1H,multiplet); 6.30-6.32 (1H, multiplet) 7.14 (1H, singlet) 7.31-7.33 (1H,multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2969, 2940, 1678,1633, 1609, 1494, 1419, 1271, 1189, 735.

EXAMPLE 24

17β-{N-[(1S)-2-(4-Methylphenyl)1-phenylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 22)

24(a)N-[(1S)-2-(4-Methylphenyl)-1-phenylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and(S)-2-(4-methylphenyl)-1-phenylethylamine as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 77%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3413, 2963, 2943,2202, 1657, 1634, 1604, 1515, 1495, 1455, 1212, 703, 554.

24(b)17β-{N-[(1S)-2-(4-Methylphenyl)-1-phenylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid

Following a procedure similar to that described in Example 1(d), butusingN-[(1S)-2-(4-methylphenyl)-1-phenylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide[prepared as described in step (a) above] as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained in a yield of 50%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.54 (3H, singlet);0.89 (3H, singlet); 0.91-2.55 (18H, multiplet); 2.29 (3H, singlet);2.98-3.12 (2H, multiplet); 5.24 (1H, quartet, J=7.3 Hz); 5.59 (1H,doublet, J=7.3 Hz); 5.85 (1H, singlet); 6.94 (2H, doublet, J=8.0 Hz);7.04 (2H, doublet, J=8.0 Hz); 7.13 (1H, singlet); 7.20-7.34 (5H,multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2942, 2913, 1669,1635, 1516, 1500, 1421, 1276, 1189, 700.

EXAMPLE 25

17β-(N,N-Dibenzylcarbamoyl)androsta-3,5-diene-3-carboxylic acid(Compound No. 4)

25(a) N,N-Dibenzyl-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 3(b), butusing S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate[prepared as described in Example 3(a)] and N,N-dibenzylamine asstarting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 80%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2943, 2929, 2904,2205, 1641, 1604, 1495, 1467, 1426, 1206, 955, 734, 696.

25(b) 17β-(N,N-Dibenzylcarbamoyl)androsta-3,5-diene-3-carboxylic acid

Following a procedure similar to that described in Example 1(d), butusing N,N-dibenzyl-3-cyanoandrosta-3,5-diene-17β-carboxamide [preparedas described in step (a) above] as a starting material, in a relativeamount similar to that used in that Example, the title compound wasobtained in a yield of 33%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.92 (6H, singlet);0.97-2.55 (17H, multiplet); 2.76 (1H, triplet, J=8.8 Hz); 3.75 (1H,doublet, J=14.6 Hz); 4.17 (1H, doublet, J=17.1 Hz); 4.95 (1H, doublet,J=17.1 Hz); 5.48 (1H, doublet, J=14.6 Hz); 5.85 (1H, singlet); 7.10-7.40(11H, multiplet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3029, 2943, 2911,1706, 1673, 1631, 1422, 1280, 1206, 1190, 701.

EXAMPLE 26

Pivaloyloxymethyl17β-{N-[1-(4-methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylate(Compound No. 145)

1 ml of pivaloyloxymethyl iodide was added, whilst ice-cooling, to 15 mlof a dimethylacetamide solution containing 196 mg of sodium17β-{N-[1-(4-methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylate(prepared by reacting the compound obtained as described in Example 2with sodium hydroxide in a conventional salification process). Theresulting solution was then stirred for 1 hour, whilst ice-cooling,after which it was diluted with ethyl acetate, washed with water, anddried over anhydrous sodium sulfate. The solvent was then removed byevaporation under reduced pressure. The resulting residue was subjectedto silica gel column chromatography using a gradient elution method,with solutions of from 1 to 3% by volume of acetone in methylenechloride as the eluent, to give 157 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.93 (3H, singlet); 1.15 (9H, singlet); 1.71 (3H, singlet); 1.72 (3H,singlet); 3.81 (3H, singlet); 5.51 (1H, singlet); 5.7-6.1 (3H,multiplet); 6.87 (2H, doublet, J=8.8 Hz); 7.12 (1H, singlet); 7.34 (2H,doublet, J=8.8 Hz).

EXAMPLE 27

Methyl 17β-[N-(diphenylmethyl)carbamoyl]androsta-3,5-diene-3-carboxylate

2 ml of methanol, 0.13 ml of triethylamine, and 110 mg ofbis(triphenylphosphine)-palladium (II) acetate were added to 8 ml of adimethylformamide solution containing 300 mg of17β-(N-diphenylmethylcarbamoyl)androsta-3,5-diene-3-trifluoromethanesulfonate(prepared as described in Preparation 5). The reaction mixture was thenstirred at room temperature under a stream of carbon monoxide for 4hours, after which it was diluted with diethyl ether, washed with water,with an aqueous solution of sodium hydrogencarbonate and with asaturated aqueous solution of sodium chloride, in that order, and driedover anhydrous magnesium sulfate. It was then concentrated byevaporation under reduced pressure. The resulting residue was subjectedto column chromatography using 20 g of silica gel and using a gradientelution method, with mixtures of acetone and methylene chloride inratios ranging from 1:99 to 3:97 by volume as the eluent, to give 214 mgof the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.90 (3H, singlet); 0.81-2.56 (18H, multiplet); 3.74 (3H, singlet); 5.79(1H, singlet); 5.91 (1H, doublet, J=7.9 Hz); 6.29 (1H, doublet, J=7.9Hz); 7.03 (1H, singlet); 7.22-7.40 (10H, multiplet).

EXAMPLE 28

17β-[N-(Diphenylmethyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid(Compound No. 2)

10 ml of water and 1 g of potassium hydroxide were added to a solutionof 25 ml of methanol containing 214 mg of methyl17β-(N-diphenylmethylcarbamoyl)androsta-3,5-diene-3-carboxylate(prepared as described in Example 27). The reaction mixture was thenheated under reflux for 4 hours. At the end of this time, methanol fromthe reaction mixture was removed by distillation under reduced pressure.The mixture was then made acidic by the addition of 1N aqueoushydrochloric acid and extracted with methylene chloride three times. Thecombined organic extracts were washed with water and with a saturatedaqueous solution of sodium chloride, in that order, dried over anhydrousmagnesium sulfate, and concentrated by evaporation under reducedpressure. The resulting residue was subjected to column chromatographyusing 20 g of silica gel and using a gradient elution method, withmixtures of acetone and methylene chloride in ratios ranging from 2:98to 50:50 by volume as the eluent, to give 110 mg of the title compound.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 1(d).

EXAMPLE 29

17β-[N-(Diphenylmethyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid(Compound No. 2)

1 ml of triethylamine, 0.5 ml of formic acid, and 110 mg ofbis(triphenylphosphine)-palladium (II) acetate were added to 10 ml of adimethylformamide solution containing 300 mg of17β-(N-diphenylmethylcarbamoyl)androsta-3,5-diene-3-trifluoromethanesulfonate(prepared as described in Preparation 5). The reaction mixture was thenstirred at room temperature under a stream of carbon monoxide for 4hours. At the end of this time, 30 ml of water were added to thereaction mixture, which was then stirred at room temperature for 1 hour,and made acidic by the addition of 1N aqueous hydrochloric acid. It wasthen extracted with methylene chloride three times. The combined organicextracts were washed with water and with a saturated aqueous solution ofsodium chloride, in that order, dried over anhydrous magnesium sulfate,and concentrated by evaporation under reduced pressure. The resultingresidue was subjected to column chromatography using 20 g of silica geland using a gradient elution method, with mixtures of acetone andmethylene chloride in ratios ranging from 2:98 to 50:50 by volume as theeluent, to give 161 mg of the title compound.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 1(d).

EXAMPLE 30

17β-{N-[1-(2-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid (Compound No. 168)

Following a procedure similar to that described in Preparation 7, butusingN-[1-(2-methoxyphenyl)-1-methylethyl]-3-formylandrosta-3,5-diene-17β-carboxamide(prepared as described in Preparation 8) as a starting material, in arelative amount similar to that used in that Preparation, the titlecompound was obtained in a yield of 37%.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 8.

EXAMPLE 31

17β-{N-[1-(3-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylic acid (Compound No. 166)

Following a procedure similar to that described in Preparation 7, butusingN-[1-(3-methoxyphenyl)-1-methylethyl]-3-formylandrosta-3,5-diene-17β-carboxamide(prepared as described in Preparation 9) as a starting material, in arelative amount similar to that used in that Preparation, the titlecompound was obtained in a yield of 54%.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 9.

PREPARATION 1

N-t-Butyl-3-oxo-4-androstene-17β-carboxamide

Following a procedure similar to that described in Example 2(b), butusing 9.77 g of S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate[prepared as described in Example 2(a)] and 14 ml of t-butylamine, 8.9 gof the title compound were obtained.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.74 (3H, singlet);1.21 (3H, singlet); 1.37 (9H, singlet); 5.11 (1H, broad singlet); 5.74(1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3450, 2965, 1674,1501.

PREPARATION 2

N-t-Butyl-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Example 2(c), butusing 100 mg of N-t-butyl-3-oxo-4-androstene-17β-carboxamide (preparedas described in Preparation 1), 0.2 ml of diethyl cyanophosphate and 200mg of a boron trifluoride-diethyl ether complex, 86 mg of the titlecompound were obtained as a crystalline substance, melting at 198° to200° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.74 (3H, singlet);0.96 (3H, singlet); 1.38 (9H, singlet); 5.08 (1H, broad singlet); 5.79(1H, broad singlet); 6.55 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3421, 2967, 2206,1669, 1499.

PREPARATION 3

17β-(N-t-Butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid

Following a procedure similar to that described in Example 2(d), butusing 250 mg of N-t-butyl-3-cyanoandrosta-3,5-diene-17β-carboxamide(prepared as described in Preparation 2), 225 mg of the title compoundwere obtained.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inPreparation 7.

PREPARATION 4

17β-(N-Diphenylmethylcarbamoyl)androsta-4-ene-3-one

Following a procedure similar to that described in Example 2(b), butusing S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [prepared asdescribed in Example 2(a)] and benzhydrylamine as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 85%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.73 (3H, singlet);0.90-2.53 (20H, multiplet); 1.19 (3H, singlet); 5.74 (1H, singlet); 5.92(1H, doublet, J=7.9 Hz); 6.30 (1H, doublet, J=7.9 Hz); 7.22-7.34 (10H,multiplet).

PREPARATION 5

17β-(N-Diphenylmethylcarbamoyl)androsta-3,5-diene-3-trifluoromethanesulfonate

0.6 g of 2,6-di-t-butyl-4-methylpyridine was added to 40 ml of a drymethylene chloride solution containing 1.0 g of17β-(N-diphenylmethylcarbamoyl)androsta-4-ene-3-one (prepared asdescribed in Preparation 4), and then 0.45 ml oftrifluoromethanesulfonic anhydride was added gradually at 0° C. under astream of nitrogen. The reaction mixture was then stirred for 30 minutesat 0° C., after which it was diluted with diethyl ether, washed with anaqueous solution of sodium hydrogencarbonate and with a saturatedaqueous solution of sodium chloride, in that order, dried over anhydrousmagnesium sulfate, and concentrated by evaporation under reducedpressure. The resulting residue was subjected to column chromatographyusing 55 g of silica gel and using a gradient elution method, withmixtures of acetone and methylene chloride in ratios ranging from 1:99to 3:97 by volume as the eluent, to give 1.1 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.71 (3H, singlet);0.96 (3H, singlet); 0.86-2.58 (18H, multiplet); 5.57 (1H, doublet, J=3.3Hz); 5.90 (1H, doublet, J=7.9 Hz); 5.98 (1H, singlet); 6.29 (1H,doublet, J=7.9 Hz); 7.22-7.36 (10H, multiplet).

PREPARATION 6

N-t-Butyl-3-formylandrosta-3,5-diene-17β-carboxamide

2 ml of a 1M solution of diisobutyl aluminum hydride in toluene wereadded at 0° C. to 10 ml of a dry solution of toluene containing 380 mgof N-t-butyl-3-cyanoandrosta-3,5-diene-17β-carboxamide (prepared asdescribed in Preparation 2). The reaction mixture was then stirred at 0°C. for 30 minutes, after which 30 ml of an aqueous solution of 1.5 g oftartaric acid were added to the mixture. The reaction mixture was thenstirred at room temperature for 2 hours, and then extracted withmethylene chloride three times. The combined organic extracts werewashed with water and with a saturated aqueous solution of sodiumchloride, in that order. They were then dried over anhydrous magnesiumsulfate, and concentrated by evaporation under reduced pressure. Theresulting residue was subjected to column chromatography using 50 g ofsilica gel and using a gradient elution method, with mixtures of acetoneand methylene chloride in ratios ranging from 1:99 to 4:96 by volume asthe eluent, to give 325 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.73 (3H, singlet);0.92 (3H, singlet); 1.05-2.60 (18H, multiplet); 1.36 (9H, singlet); 5.09(1H, broad singlet); 5.98 (1H, triplet, J=3.0 Hz); 6.78 (1H, doublet,J=2.0 Hz); 9.47 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2964, 2943, 2905,1671, 1631, 1501, 1451, 1385, 1252, 1220, 1171, 716, 646.

PREPARATION 7

17β-(N-t-Butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid

600 mg of sodium phosphate dihydrate and 1.2 g of sodium chlorite wereadded, in that order, at room temperature to a mixture of 7.5 ml oft-butanol, 2.0 ml of water and 1 ml of 2-methyl-2-butene containing 400mg of N-t-butyl-3-formylandrosta-3,5-diene-17β-carboxamide (prepared asdescribed in Preparation 6). The reaction mixture was then stirred for15 minutes. At the end of this time, the reaction mixture was quenchedby pouring it into a ice-cooled aqueous solution of sodium thiosulfate;it was then made acidic by the addition of 1N aqueous hydrochloric acid,and extracted with ethyl acetate three times. The combined organicextracts were washed with water and with a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate, andconcentrated by evaporation under reduced pressure. The resultingresidue was crystallized by the addition of diethyl ether, to give 225mg of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.73 (3H, singlet);0.92 (3H, singlet); 1.05-2.55 (18H, multiplet); 1.35 (9H, singlet); 5.09(1H, broad singlet); 5.86 (1H, singlet); 7.14 (1H, singlet).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 2964, 2939, 2910,1671, 1633, 1612, 1505, 1450, 1420, 1364, 1278, 1223, 1190, 926, 640.

PREPARATION 8

N-[1-(2-Methoxyphenyl)-1-methylethyl]-3-formylandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Preparation 6, butusingN-[1-(2-methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in Example 8(a)] as a starting material, in arelative amount similar to that used in that preparation, the titlecompound was obtained in a yield of 74%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.67 (3H, singlet);0.92 (3H, singlet); 1.04-2.54 (18H, multiplet); 1.77 (3H, singlet); 1.81(3H, singlet); 3.83 (3H, singlet); 5.94 (1H, singlet); 5.98 (1H,triplet, J=3.0 Hz); 6.78 (1H, singlet); 6.88-6.97 (2H, multiplet);7.21-7.26 (1H, multiplet); 7.40 (1H, doublet of doublets, J=8.0 & 1.0Hz); 9.47 (1H, singlet).

PREPARATION 9

N-[1-(3-Methoxyphenyl)-1-methylethyl]-3-formylandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Preparation 6, butusingN-[1-(3-methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide[prepared as described in Example 9(a)] as a starting material, in arelative amount similar to that used in that Preparation, the titlecompound was obtained in a yield of 95%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.73 (3H, singlet);0.93 (3H, singlet); 1.00-2.56 (18H, multiplet); 1.70 (3H, singlet); 1.72(3H, singlet); 3.80 (3H, singlet); 5.53 (1H, singlet); 5.97 (1H,singlet); 6.76-6.84 (2H, multiplet); 6.96-7.01 (2H, multiplet);7.22-7.28 (1H, multiplet); 9.47 (1H, singlet).

PREPARATION 10a

1-(4-Methoxyphenyl)-1-methylethylamine

10(a) (i) 1-(4-Methoxyphenyl)-1-methylethyl azide

A solution containing 25 g of methyl 4-methoxybenzoate in 100 ml of drytetrahydrofuran was added dropwise, whilst ice-cooling, to 300 ml of a1N solution of methyl magnesium bromide in tetrahydrofuran. The reactionmixture was then stirred at room temperature for 30 minutes. At the endof this time, an aqueous solution of ammonium chloride was added to thereaction mixture, which was then stirred for 10 minutes, and extractedthree times with diethyl ether. The organic extract was washed withwater and with a saturated aqueous solution of sodium chloride, in thatorder, after which it was dried over anhydrous magnesium sulfate, andconcentrated by evaporation under reduced pressure. The resultingresidue was dissolved in a mixture of 200 ml of chloroform and 100 ml ofacetone, 20 g of sodium azide were added to this solution, and then 60ml of trifluoroacetic acid and 100 ml of chloroform were added dropwise,whilst ice-cooling and stirring, to the mixture. The mixture was stirredat room temperature for 2 hours, after which it was allowed to standovernight at room temperature. Water was then added to the mixture, andthe mixture was neutralized by the addition of potassium carbonate. Itwas then extracted three times with methylene chloride. The combinedorganic extracts were washed with water and with a saturated aqueoussolution of sodium chloride, in that order, dried over anhydrousmagnesium sulfate, and concentrated by evaporation under reducedpressure. The resulting residue was subjected to column chromatographyusing 300 g of silica gel and using a gradient elution method, withmixtures of diethyl ether and hexane in ratios ranging from 1:99 to 4:96by volume as the eluent, to give 21.0 g (yield 73.8%) of the titlecompound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.61 (6H, singlet);3.81 (3H, singlet); 6.89 (2H, doublet, J=9 Hz); 7.36 (2H, doublet, J=9Hz).

10 (a) (ii) 1-(4-Methoxyphenyl)-1-methylethylamine

1.58 g of platinum oxide were added to a solution of 21.0 g of1-(4-methoxyphenyl)-1-methylethyl azide [prepared as described in step(a) above] in 100 ml of methanol. The reaction mixture was then stirredfor 5 hours under a stream of hydrogen. At the end of this time, themixture was filtered, diluted with methylene chloride, and washed withan aqueous solution of sodium hydrogencarbonate, with water and with asaturated aqueous solution of sodium chloride, in that order. It wasthen dried over anhydrous magnesium sulfate, and concentrated byevaporation under reduced pressure, to give 17.2 g (yield 95%) of thetitle compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.49 (6H, singlet);1.89 (2H, singlet); 3.80 (3H, singlet); 6.86 (2H, doublet, J=9 Hz); 7.43(2H, doublet, J=9 Hz).

Infrared Absorption Spectrum (KBr), ν_(cm) ⁻¹ : 2963, 2936, 1611, 1513,1298, 1248, 1183, 1035, 831.

PREPARATION 10b

1-(3-Methoxyphenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 3-methoxybenzoate as a starting material, in a relativeamount similar to that used in that Preparation, the title compound wasobtained in a yield of 31%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.49 (6H, singlet);1.81 (2H, broad singlet); 3.82 (3H, singlet); 6.74-6.79 (1H, multiplet);7.06-7.10 (2H, multiplet); 7.22-7.29 (1H, multiplet).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2964, 1602,1582, 1487, 1430, 1289, 1250, 1048, 872, 782, 702.

PREPARATION 10c

1-(2-Methoxyphenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 2-methoxybenzoate as a starting material, in a relativeamount similar to that used in that Preparation, the title compound wasobtained in a yield of 81%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.53 (6H, singlet);2.06 (2H, broad singlet); 3.88 (3H, singlet); 6.89-6.93 (2H, multiplet);7.19-7.24 (1H, multiplet); 7.32-7.35 (1H, multiplet).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2965, 1597,1581, 1489, 1464, 1436, 1236, 1028, 754.

PREPARATION 10d

1-(3,5-Dimethoxyphenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 3,5-dimethoxybenzoate as a starting material, in a relativeamount similar to that used in that Preparation, the title compound wasobtained in a yield of 75%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.48 (6H, singlet);1.81 (2H, broad singlet); 3.80 (6H, singlet); 6.34 (1H, triplet, J=2Hz); 6.66 (2H, doublet, J=2 Hz).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2694, 1596,1457, 1423, 1204, 1154, 1053, 854, 699.

PREPARATION 10e

1-(3,4-Dimethoxyphenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 3,4-dimethoxybenzoate, in a relative amount similar to thatused in that Preparation, the title compound was obtained in a yield of61%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.49 (6H, singlet);1.73 (2H, broad singlet); 3.87 (3H, singlet); 3.91 (3H, singlet); 6.82(1H, doublet, J=8 Hz); 7.01 (1H, doublet of doublets, J=2 & 8 Hz); 7.10(1H, doublet, J=2 Hz).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2963, 1604,1519, 1510, 1258, 1147, 1028, 766, 649.

PREPARATION 10f

1-(4-Fluorophenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 4-fluorobenzoate as a starting material, in a relativeamount similar to that used in that Preparation, the title compound wasobtained in a yield of 20%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.48 (6H, singlet);1.63 (2H, broad singlet); 6.96-7.03 (2H, multiplet); 7.44-7.50 (2H,multiplet).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2967, 1601,1509, 1228, 1162, 835, 809, 551.

PREPARATION 10g

1-(4-Ethoxyphenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 4-ethoxybenzoate as a starting material, in a relativeamount similar to that used in that Preparation, the title compound wasobtained in a yield of 60%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.40 (3H, triplet,J=7 Hz); 1.48 (6H, singlet); 1.68 (2H, broad singlet); 4.02 (2H,quartet, J=7 Hz); 6.82-6.88 (2H, multiplet); 7.37-7.43 (2H, multiplet).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2977, 1609,1512, 1245, 1183, 1048, 834, 560.

PREPARATION 10h

1-(4-Methylphenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 4-methylbenzoate as a starting material, in a relativeamount similar to that used in that Preparation, the title compound wasobtained in a yield of 34%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.48 (6H, singlet);1.62 (2H, broad singlet); 2.33 (3H, singlet); 7.14 (2H, doublet, J=9Hz); 7.39 (2H, doublet, J=9 Hz) .

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2965, 1587,1514, 1360, 1189, 1115, 1020, 817, 722, 552.

PREPARATION 10i

1-(4-N,N-Dimethylaminophenyl)-1-methylethylamine

Following a procedure similar to that described in Preparation 10a, butusing methyl 4-N,N-dimethylaminobenzoate as a starting material, in arelative amount similar to that used in that Preparation, the titlecompound was obtained in a yield of 48%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.48 (6H, singlet);1.70 (2H, broad singlet); 2.95 (6H, singlet); 6.65-6.80 (2H, multiplet);7.30 (2H, doublet, J=9 Hz).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2960, 1615,1525, 815.

PREPARATION 11a

1-Methyl-1-(2-thienyl)ethylamine

11(a) (i) Methyl 2-methyl-2-(2-thienyl)propionate 9.2 g of sodiumhydride (as a 55% w/w dispersion in mineral oil) were washed with hexaneand mixed with 140 ml of a dry dimethylformamide. 30 ml of a solution of15 g of methyl 2-thiophene acetate in dimethylformamide were then addeddropwise, whilst ice-cooling, to this mixture. The resulting mixture wasstirred at room temperature for 30 minutes, and cooled. 18 ml of methyliodide were gradually added dropwise, and the mixture was stirred atroom temperature overnight. It was then poured into ice-water andextracted three times with diethyl ether. The combined organic extractswere washed with water and with a saturated aqueous solution of sodiumchloride, in that order, dried over anhydrous magnesium sulfate, andconcentrated by evaporation under reduced pressure, to give 17.5 g ofthe title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 3.68 (3H, singlet);6.93-6.95 (2H, multiplet); 7.18-7.21 (1H, multiplet). 11(a) (ii)2-Methyl-2-(2-thienyl)propionic acid

A solution containing 17.5 g of methyl 2-methyl-2-(2-thienyl)propionate[prepared as described in step (i) above], 12.6 g of potassiumhydroxide, 72 ml of water, and 168 ml of 1,4-dioxane was heated underreflux for 2 hours. At the end of this time, it was diluted withice-water, and extracted twice with diethyl ether. The aqueous layer wasadjusted to a weakly acidic pH, extracted three times with diethylether, washed with water and with a saturated aqueous solution of sodiumchloride, in that order, dried over anhydrous magnesium sulfate, andconcentrated by evaporation under reduced pressure to give 15.8 g of thetitle compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.68 (6H, singlet);6.93-7.02 (2H, multiplet); 7.19-7.23 (1H, multiplet).

11(a) (iii) 2-Methyl-2-(2-thienyl)propionylazide

10.6 ml of ethyl chlorocarbonate were gradually added, keeping thetemperature below 0° C., to a solution of 15.8 g of2-methyl-2-(2-thienyl)propionic acid [prepared as described in step (ii)above] and 15.6 ml of triethylamine in 210 ml of acetone. The reactionmixture was stirred at 0° C. for 2 hours, after which 10 ml of anaqueous solution containing 10.3 g of sodium azide were added to themixture at 0° C. The reaction mixture was then stirred at 0° C. for 2hours, diluted with water, and extracted three times with diethyl ether.The combined organic extracts were washed with 1N aqueous hydrochloricacid, with an aqueous solution of sodium hydrogencarbonate, and with asatulated solution of sodium chloride, in that order, after which it wasdried over anhydrous magnesium sulfate, and concentrated by evaporationunder reduced pressure to give 18.5 g of the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.66 (6H, singlet);6.91-7.00 (2H, multiplet); 7.18-7.25 (1H, multiplet).

11(a) (iv) 1-Methyl-1-(2-thienyl)ethylamine

A solution of 370 ml of dry benzene and 18.5 g of2-methyl-2-(2-thienyl)propionylazide [prepared as described in step(iii) above] was heated under reflux for 4 hours. At the end of thistime, the solvent was removed from the reaction mixture to a finalvolume of 270 ml by evaporation under reduced pressure. 97 ml ofconcentrated aqueous hydrochloric acid were then added to the remainingsolution, whilst ice-cooling, and the reaction mixture was stirred atroom temperature for 5 hours. At the end of this time, it was dilutedwith water, and extracted twice with diethyl ether. The remainingaqueous layer was adjusted to a basic pH value by the addition of anaqueous solution of potassium hydroxide. It was then extracted threetimes with diethyl ether, washed with a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate, andconcentrated by evaporation under reduced pressure to give 8.4 g of thetitle compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.57 (6H, singlet);1.76 (2H, broad singlet); 6.89-6.94 (2H, multiplet); 7.13-7.16 (1H,multiplet).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2966, 1589,1465, 1362, 1241, 852, 826, 697.

PREPARATION 11b

1-Methyl-1-(3-thienyl)ethylamine

Following a procedure similar to that described in Preparation 11a, butusing methyl 3-thienylacetate as a starting material, in a relativeamount similar to that used in that Preparation, the title compound wasobtained in a yield of 32%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.48 (6H, singlet);1.61 (2H, singlet); 7.09-7.14 (1H, multiplet); 7.25-7.29 (2H,multiplet).

Infrared Absorption Spectrum (CHCl₃), ν_(max) cm⁻¹ : 3350, 3260, 2940,1580.

PREPARATION 11c

α,α-Dimethylfurfurylamine

Following a procedure similar to that described in

Preparation 11a, but using ethyl 1-(2-furyl)propionate as a startingmaterial, in a relative amount similar to that used in that Preparation,the title compound was obtained in a yield of 40%.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 1.46 (6H, singlet);1.66 (2H, singlet); 6.05-6.07 (1H, multiplet); 6.26-6.29 (1H,multiplet); 7.31-7.33 (1H, multiplet).

Infrared Absorption Spectrum (CHCl₃), ν_(max) cm⁻¹ : 3300, 2960, 1710,1590.

PREPARATION 12

4,4'-Difluorobenzhydrylamine

57.04 g of ammonium acetate and 12.69 g of sodium cyanoborohydride wereadded to a solution of 15.68 g of 4-fluorobenzophenone oxime in 315 mlof methanol. The mixture was stirred at room temperature, and then 135ml of a 17-19% by volume aqueous solution of titanium trichloride wereadded dropwise over a period of 4 hours and 50 minutes. The reactionmixture was stirring for 1.5 hours, diluted with water and extractedwith methylene chloride. The aqueous extract was adjusted to a basic pHvalue by the addition of an aqueous solution of sodium hydroxide andextracted with methylene chloride. At this point, the precipitate wasremoved by filtration using a Celite (trade mark) filter aid. Thefiltrate was dried over anhydrous magnesium sulfate and concentrated byevaporation under reduced pressure. The resulting residue was subjectedto silica gel column chromatography using a gradient elution method,with solutions of acetone in methylene chloride in proportions rangingfrom 2-5% by volume as the eluent, to give 11.66 g (yield 79%) of thetitle compound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 5.11 (1H, singlet);6.92 (4H, multiplet); 7.25 (4H, multiplet).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1602, 1506,1223, 1155.

Mass Spectrum (m/z): 219 (M⁺), 203, 201, 138, 123.

PREPARATION 13

4-Hydroxybenzhydrylamine

A procedure similar to that described in Preparation 12 was repeated,but using 86 ml of a methanolic solution containing 4.28 g of4-hydroxybenzophenone oxime, 17.03 g of ammonium acetate, 3.79 g ofsodium cyanoborohydride, and 40.1 ml of a 17-19% by volume aqueoussolution of titanium trichloride, and using a dilute aqueous solution ofsodium hydrogencarbonate instead of the aqueous solution of sodiumhydroxide, and using ethyl acetate as the extracting solvent. Theresidue obtained was subjected to silica gel column chromatography andeluted with a 80% by volume solution of ethyl acetate in hexane, withethyl acetate itself, and with a 3% by volume solution of methanol inethyl acetate, to give 2.74 g of the title compound as crystals, meltingat 113° -115° C. (after recrystallization from methylene chloride).

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide),δ ppm: 5.0 (1H, singlet); 6.68 (2H, doublet, J=9 Hz); 7.1-7.5 (7H,multiplet).

Infrared Absorption Spectrum (Nujol-trade mark), ν_(max) cm⁻¹ : 3336,2923, 1609, 1591, 1576, 1248.

Elemental analysis: Calculated for C₁₃ H₁₃ NO: C, 78.36%; H, 6.58%; N,7.03%. Found: C, 77.97%; H, 6.61%; N, 6.93%.

PREPARATION 14

4,4'-Dimethoxybenzhydrylamine

Following a procedure similar to that described in Preparation 12, butusing 10.7 g of 4,4'-dimethoxybenzophenone oxime, 33.9 g of ammoniumacetate, 7.46 g of sodium cyanoborohydride, and 79 ml of a 17-19% byvolume aqueous solution of titanium trichloride, 8.18 g of the titlecompound were obtained, as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 3.78 (6H, singlet);5.09 (1H, singlet); 6.85 (4H, doublet, J=9 Hz); 7.26 (4H, doublet, J=9Hz).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 2953, 2834,1608, 1583, 1508, 1246.

Mass Spectrum (m/z): 243 (M⁺), 242, 227.

PREPARATION 15

4-Methoxybenzhydrylamine

Following a procedure similar to that described in Preparation 12, butusing 9.4 g of 4-methoxybenzophenone oxime, 33.9 g of ammonium acetate,7.46 g of sodium cyanoborohydride, and 79 ml of a 17-19% by volumeaqueous solution of titanium trichloride, 6.78 g of the title compoundwere obtained as an oily substance.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 3.76 (3H, singlet);5.10 (1H, singlet); 6.84 (2H, doublet, J=9 Hz); 7.1-7.5 (7H, multiplet).

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 3025, 2834,1609, 1584, 1509, 1247.

Mass Spectrum (m/z): 213 (M⁺), 197, 182, 136.

PREPARATION 16a

N-(Diphenylmethyl)-3-cyanoandrosta-3,5-diene-17β-carboxamide

0.106 ml of benzhydrylamine were added to a solution of 100 mg of3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described inExample 1(b)], a catalytic amount of 4-dimethylaminopyridine and 0.131ml of triethylamine in 4 ml of methylene chloride. 88.0 mg of tosylchloride were then divided into three portions and added to thisreaction mixture at 30 minute intervals at room temperature, whilststirring. One hour after finishing the addition of the tosyl chloride,the reaction mixture was diluted with methylene chloride, and washedwith 1N aqueous hydrochloric acid, with water, with an aqueous solutionof sodium hydrogencarbonate, and with a saturated aqueous solution ofsodium chloride, in that order. It was then dried over anhydrousmagnesium sulfate, and concentrated by evaporation under reducedpressure. The resulting residue was crystallized from acetone, to give138 mg (yield 92%) of the title compound.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 1(c).

PREPARATION 16b

N-t-Butyl-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Preparation 16a, butusing 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared asdescribed in Example 1(b)] and t-butylamine as starting materials, inrelative proportions similar to those used in that Preparation, thetitle compound was obtained in a yield of 81%.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inPreparation 2.

PREPARATION 16c

N-[1-(3,5-Dimethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide

Following a procedure similar to that described in Preparation 16a, butusing 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared asdescribed in Example 1(b)] and1-(3,5-dimethoxyphenyl)-1-methylethylamine as starting materials, inrelative proportions similar to those used in that Preparation, thetitle compound was obtained in a yield of 98%.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 10(a).

PREPARATION 16d

N-[1-(4-Methoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Preparation 16a, butusing 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared asdescribed in Example 1(b)] and 1-(4-methoxyphenyl)-1-methylethylamine asstarting materials, in relative proportions similar to those used inthat Preparation, the title compound was obtained in a yield of 93%.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 2(c).

PREPARATION 16e

N-[1-Methyl-1-phenylethyl]-3-cyanoandrosta-3,5-diene-17β-carboxamide

Following a procedure similar to that described in Preparation 16a, butusing 3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared asdescribed in Example 1(b)] and 1-methyl-1-phenylethylamine as startingmaterials, in relative proportions similar to those used in thatPreparation, the title compound was obtained in a yield of 74%.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 4(a).

PREPARATION 16f

N-[1-(3,5-Dimethoxyphenyl)-1-methylethyl]-3-cyanoandrosta-3,5-diene-17.beta.-carboxamide

Vilsmeier reagent was prepared from 1.7 ml of dimethylformamide, 1.8 mlof phosphorus oxychloride, and 5 ml of methylene chloride. 0.23 ml ofthis Vilsmeier reagent was then added to a solution of 100 mg of3-cyanoandrosta-3,5-diene-17β-carboxylic acid [prepared as described inExample 1(b)] in 2 ml of methylene chloride. The reaction mixture wasthen stirred at room temperature for 40 minutes, after which a solutionof 1-(3,5-dimethoxyphenyl)-1-methylethylamine [prepared as described inPreparation 10(d)] and 70 μl of triethylamine in 2 ml of methylenechloride were added. The reaction mixture was then diluted with ethylacetate, washed with dilute aqueous hydrochloric acid, with an aqueoussolution of sodium chloride, with a 5% w/v aqueous solution of sodiumhydrogencarbonate, and with a saturated aqueous solution of sodiumchloride, in that order. It was then dried over anhydrous magnesiumsulfate, and concentrated by evaporation under reduced pressure. Theresulting residue was subjected to silica gel column chromatography andusing a gradient elution method, with solutions of from 1 to 4% byvolume of acetone in methylene chloride as the eluent, to give 76 mg(yield 50%) of the title compound.

The Nuclear Magnetic Resonance Spectrum and Infrared Absorption Spectrumdata are identical with those of the compound obtained as described inExample 10(a).

PREPARATION 17

N-(Diphenylmethyl)androsta-4-ene-3-one-17β-carboxamide

0.108 ml of benzhydrylamine was added to a solution of 100 mg ofandrosta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml ofmethylene chloride. 0.037 ml of methanesulfonyl chloride was dividedinto three portions and added to this reaction mixture at intervals of30 minutes at room temperature, whilst stirring. One hour afterfinishing the addition of methanesulfonyl chloride, the reaction mixturewas diluted with methylene chloride, washed with 1N aqueous hydrochloricacid, with water, with an aqueous solution of sodium hydrogencarbonateand with a saturated aqueous solution of sodium chloride, in that order.It was then dried over anhydrous magnesium sulfate, and concentrated byevaporation under reduced pressure. The resulting residue wascrystallized from acetone to give 113.2 mg (yield 74%) of the titlecompound.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm: 0.72 (3H, singlet);0.77-2.44 (20H, multiplet); 1.18 (3H, singlet); 5.73 (1H, singlet); 5.88(1H, doublet, J=8 Hz); 6.28 (1H, doublet, J=8 Hz); 7.21-7.36 (10H,multiplet).

Infrared Absorption Spectrum (KBr) , ν_(cm) ⁻¹ : 2941, 2875, 1665, 1616,1518, 1495, 1449, 1230, 699.

PREPARATION 18

N-(Diphenylmethyl)androsta-4-ene-3-one-17β-carboxamide

0.108 ml of benzhydrylamine was added to a solution of 100 mg ofandrosta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml ofmethylene chloride. 0.050 ml of trifluoromethanesulfonyl chloride wasdivided into three portions and added to this reaction mixture atintervals of 30 minutes at room temperature, whilst stirring. One hourafter finishing the addition of trifluoromethanesulfonyl chloride, thereaction mixture was diluted with methylene chloride, washed with 1 Naqueous hydrochloric acid, with water, with an aqueous solution ofsodium hydrogencarbonate and with a saturated aqueous solution of sodiumchloride, in that order. It was then dried over anhydrous magnesiumsulfate, and concentrated by evaporation under reduced pressure. Theresulting residue was crystallized from acetone to give 135.2 mg (yield89%) of the title compound, having the same properties as the product ofPreparation 17.

PREPARATION 19

N-(Diphenylmethyl)androsta-4-ene-3-one-17β-carboxamide 0.108 ml ofbenzhydrylamine was added to a solution of 100 mg ofandrosta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml ofmethylene chloride. 0.060 ml of benzenesulfonyl chloride was dividedinto three portions and added to this reaction mixture at intervals of30 minutes at room temperature, whilst stirring. One hour afterfinishing the addition of benzenesulfonyl chloride, the reaction mixturewas diluted with methylene chloride, washed with 1N aqueous hydrochloricacid, with water, with an aqueous solution of sodium hydrogencarbonateand with a saturated aqueous solution of sodium chloride, in that order.It was then dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The resulting residue was crystallized fromacetone to give 130.1 mg (yield 85%) of the title compound, having thesame properties as the product of Preparation 17.

We claim:
 1. A compound of formula (I): ##STR13## wherein: R¹represents: a hydrogen atom; an alkyl group having from 1 to 6 carbonatoms; or a substituted alkyl group having from 1 to 6 carbon atoms andhaving at least one substituent selected from the group consisting ofaryl groups as defined below and aromatic heterocyclic groups as definedbelow;R² represents: a substituted alkyl group having from 1 to 6 carbonatoms and having at least one substituent selected from the groupconsisting of aryl groups as defined below and aromatic heterocyclicgroups as defined below, and said alkyl group further optionally havinga single hydroxy or carboxy substituent; or a diarylamino group in whichthe two aryl parts are the same or different and each is as definedbelow;R³ represents a carboxy group or a group of formula --CONHSO₂ R⁴wherein R⁴ represents an alkyl group having from 1 to 6 carbon atoms;said aryl groups are carbocyclic aromatic groups having from 6 to 14ring carbon atoms and which are unsubstituted or are substituted by atleast one substituent selected from the group consisting of substituentsA, defined below; said aromatic heterocyclic groups have 5 or 6 ringatoms of which from 1 to 3 are hetero-atoms selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms and the remainderare carbon atoms, said group being unsubstituted or being substituted byat least one substituent selected from the group consisting ofsubstituents B, defined below; said substituents A are selected from thegroup consisting of: alkyl groups having from 1 to 6 carbon atoms;alkoxy groups having from 1 to 6 carbon atoms; alkoxycarbonyl groupshaving from 2 to 7 carbon atoms; hydroxy groups; halogen atoms; aminogroups; alkylamino groups having from 1 to 6 carbon atoms; dialkylaminogroups in which each alkyl part has from 1 to 6 carbon atoms; aliphaticacylamino groups having from 1 to 6 carbon atoms; aromatic acylaminogroups in which the aromatic part is a carbocyclic aryl group which hasfrom 6 to 10 ring carbon atoms and which is unsubstituted or issubstituted by at least one substituent selected from the groupconsisting of substituents C, defined below; cyano groups; nitro groups;and carboxy groups; said substituents B are selected from the groupconsisting of: alkyl groups having from 1 to 6 carbon atoms; alkoxygroups having from 1 to 6 carbon atoms; hydroxy groups; halogen atoms;carbocyclic aryl groups which have from 6 to 10 ring carbon atoms andwhich are unsubstituted or are substituted by at least one substituentselected from the group consisting of substituents C, defined below;amino groups; alkylamino groups having from 1 to 6 carbon atoms;dialkylamino groups in which each alkyl part has from 1 to 6 carbonatoms; aliphatic acylamino groups having from 1 to 6 carbon atoms;aromatic acylamino groups in which the aromatic part is a carbocyclicaryl group which has from 6 to 10 ring carbon atoms and which isunsubstituted or is substituted by at least one substituent selectedfrom the group consisting of substituents C, defined below; nitrogroups; and carboxy groups; said substituents C are selected from thegroup consisting of: alkyl groups having from 1 to 6 carbon atoms;alkoxy groups having from 1 to 6 carbon atoms; hydroxy groups; halogenatoms; amino groups; alkylamino groups having from 1 to 6 carbon atoms;dialkylamino groups in which each alkyl part has from 1 to 6 carbonatoms; aliphatic acylamino groups having from 1 to 6 carbon atoms; cyanogroups; nitro groups; and carboxy groups; or a pharmaceuticallyacceptable salt or ester thereof.
 2. The compound of claim 1, wherein R¹represents:a hydrogen atom; an alkyl group having 3 carbon atoms; abenzyl group; a substituted benzyl group having on the aromatic ring atleast one substituent selected from the group consisting of alkyl groupshaving from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbonatoms, halogen atoms, amino groups, alkylamino groups having from 1 to 4carbon atoms, dialkylamino groups in which each alkyl part has from 1 to4 carbon atoms, hydroxy groups, alkoxycarbonyl groups having from 2 to 5carbon atoms and aliphatic acylamino groups having from 1 to 5 carbonatoms; a furylmethyl group; or a thienylmethyl group.
 3. The compound ofclaim 1, wherein R² represents:a substituted alkyl group having from 1to 4 carbon atoms and substituted by 1 or 2 substituents selected fromthe group consisting of phenyl groups, substituted phenyl groups,thienyl groups, furyl groups, substituted thienyl groups and substitutedfuryl groups, wherein the substituent or substituents on the phenylgroup are selected from the group consisting of:alkyl groups having from1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms,halogen atoms, hydroxy groups, amino groups, alkylamino groups havingfrom 1 to 4 carbon atoms, dialkylamino groups in which each alkyl parthas from 1 to 4 carbon atoms, alkoxycarbonyl groups having from 2 to 5carbon atoms and aliphatic acylamino groups having from 1 to 5 carbonatoms; and the substituent or substituents on the thienyl and furylgroups are selected from the group consisting of alkyl groups havingfrom 1 to 4 carbon atoms; or a diarylamino group, in which each arylpart is a carbocyclic aromatic group which has from 6 to 10 ring carbonatoms and which is unsubstituted or is substituted by at least onesubstituent selected from the group consisting ofalkyl groups havingfrom 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms,halogen atoms, hydroxy groups, amino groups, alkylamino groups havingfrom 1 to 4 carbon atoms, dialkylamino groups in which each alkyl parthas from 1 to 4 carbon atoms, alkoxycarbonyl groups having from 2 to 5carbon atoms and aliphatic acylamino groups having from 1 to 5 carbonatoms.
 4. The compound of claim 1, wherein R³ represents:a carboxygroup; an alkoxycarbonyl group having from 2 to 5 carbon atoms; abenzyloxycarbonyl group; a substituted benzyloxycarbonyl group at leastone substituent selected from the group consisting of methyl, ethyl,methoxy and ethoxy groups and fluorine and chlorine atoms; anaphthylmethoxycarbonyl group; a diphenylmethoxycarbonyl group; analkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from 1 to5 carbon atoms and the alkoxy part has from 1 to 4 carbon atoms; acycloalkanecarbonyloxyalkoxycarbonyl group in which the cycloalkane parthas from 5 to 7 carbon atoms and the alkoxy part has from 1 to 4 carbonatoms; an alkoxycarbonyloxyalkoxycarbonyl group in which each alkoxypart has from 1 to 4 carbon atoms; acycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloalkylpart has from 5 to 7 carbon atoms and the alkoxy part has from 1 to 4carbon atoms; a (5-phenyl- or5-alkyl-2-oxo-1,3-dioxolen-4-yl)-methoxycarbonyl group in which thealkyl part has from 1 to 4 carbon atoms; a phthalidyloxycarbonyl group;or a group of formula --CONHSO₂ R⁴ wherein R⁴ represents an alkyl grouphaving from 1 to 4 carbon atoms.
 5. The compound of claim 1, wherein:R¹represents: a hydrogen atom; an alkyl group having 3 carbon atoms; abenzyl group; a substituted benzyl group having at least one substituentselected from the group consisting of alkyl groups having from 1 to 4carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogenatoms, amino groups, alkylamino groups having from 1 to 4 carbon atoms,dialkylamino groups in which each alkyl part has from 1 to 4 carbonatoms, hydroxy groups, alkoxycarbonyl groups having from 2 to 5 carbonatoms and aliphatic acylamino groups having from 1 to 5 carbon atoms; afurylmethyl group; or a thienylmethyl group;R² represents: a substitutedalkyl group having from 1 to 4 carbon atoms and substituted by 1 or 2substituents selected from the group consisting of phenyl groups,substituted phenyl groups, thienyl groups, furyl groups, substitutedthienyl groups and substituted furyl groups, wherein the substituent orsubstituents on the phenyl group are selected from the group consistingof:alkyl groups having from 1 to 4 carbon atoms, alkoxy groups havingfrom 1 to 4 carbon atoms, halogen atoms, hydroxy groups, amino groups,alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groupsin which each alkyl part has from 1 to 4 carbon atoms, alkoxycarbonylgroups having from 2 to 5 carbon atoms and aliphatic acylamino groupshaving from 1 to 5 carbon atoms; and the substituent or substituents onthe thienyl and furyl groups are selected from the group consisting ofalkyl groups having from 1 to 4 carbon atoms; or a diarylamino group, inwhich each aryl part is a carbocyclic aromatic group which has from 6 to10 ring carbon atoms and which is unsubstituted or is substituted by atleast one substituent selected from the group consisting ofalkyl groupshaving from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbonatoms, halogen atoms, hydroxy groups, amino groups, alkylamino groupshaving from 1 to 4 carbon atoms, dialkylamino groups in which each alkylpart has from 1 to 4 carbon atoms, alkoxycarbonyl groups having from 2to 5 carbon atoms and aliphatic acylamino groups having from 1 to 5carbon atoms; andR³ represents: a carboxy group; an alkoxycarbonyl grouphaving from 2 to 5 carbon atoms; a benzyloxycarbonyl group; asubstituted benzyloxycarbonyl group at least one substituent selectedfrom the group consisting of methyl, ethyl, methoxy and ethoxy groupsand fluorine and chlorine atoms; a naphthylmethoxycarbonyl group; adiphenylmethoxycarbonyl group; an alkanoyloxyalkoxycarbonyl group inwhich the alkanoyl part has from 1 to 5 carbon atoms and the alkoxy parthas from 1 to 4 carbon atoms; a cycloalkanecarbonyloxyalkoxycarbonylgroup in which the cycloalkane part has from 5 to 7 carbon atoms and thealkoxy part has from 1 to 4 carbon atoms; analkoxycarbonyloxyalkoxycarbonyl group in which each alkoxy part has from1 to 4 carbon atoms; a cycloalkyloxycarbonyloxyalkoxycarbonyl group inwhich the cycloalkyl part has from 5 to 7 carbon atoms and the alkoxypart has from 1 to 4 carbon atoms; a (5-phenyl- or5-alkyl-2-oxo-1,3-dioxolen-4-yl)-methoxycarbonyl group in which thealkyl part has from 1 to 4 carbon atoms; a phthalidyloxycarbonyl group;or a group of formula --CONHSO₂ R⁴, wherein R⁴ represents an alkyl grouphaving from 1 to 4 carbon atoms.
 6. The compound of claim 1, wherein R¹represents:a hydrogen atom; an isopropyl group; a benzyl group; asubstituted benzyl group having at least one substituent selected fromthe group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy,ethoxycarbonyl, methoxycarbonyl, amino, methylamino, ethylamino,dimethylamino, diethylamino, formamido and acetamido groups andfluorine, chlorine and bromine atoms; or a thienylmethyl group.
 7. Thecompound of claim 1, wherein R² represents:a substituted alkyl grouphaving from 1 to 4 carbon atoms and having 1 or 2 substituents selectedfrom the group consisting of:phenyl groups; substituted phenyl groupshaving at least one substituent selected from the group consisting ofmethyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl,ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino,diethylamino, formamido and acetamido groups and fluorine, chlorine andbromine atoms; furyl groups; methyl-substituted furyl groups thienylgroups; and methyl-substituted thienyl groups; a diphenylamino group; ora substituted diphenylamino group having at least one substituentselected from the group consisting of methyl, ethyl, methoxy, ethoxy,hydroxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino,ethylamino, dimethylamino, diethylamino, formamido and acetamido groupsand fluorine, chlorine and bromine atoms.
 8. The compound of claim 1,wherein R³ represents:a carboxy group; an alkoxycarbonyl group havingfrom 2 to 5 carbon atoms; a benzyloxycarbonyl group; analkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from 1 to5 carbon atoms and the alkoxy part has 1 or 2 carbon atoms; acycloalkanecarbonyloxyalkoxycarbonyl group in which the cycloalkane parthas from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms; a methoxycarbonyl or ethoxycarbonyl group which is substituted byan alkoxycarbonyloxy group having from 2 to 5 carbon atoms; acycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloalkylpart has from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms; a (5-phenyl-, 5-methyl- or5-ethyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group; aphthalidyloxycarbonyl group; or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents a methyl group or an ethyl group.
 9. The compound of claim1, wherein:R¹ represents: a hydrogen atom; an isopropyl group; a benzylgroup; a substituted benzyl group having on the aromatic ring at leastone substituent selected from the group consisting of methyl, ethyl,methoxy, ethoxy, hydroxy, ethoxycarbonyl, methoxycarbonyl, amino,methylamino, ethylamino, dimethylamino, diethylamino, formamido andacetamido groups and fluorine, chlorine and bromine atoms; or athienylmethyl group;R² represents: a substituted alkyl group having from1 to 4 carbon atoms and having 1 or 2 substituents selected from thegroup consisting of:phenyl groups; substituted phenyl groups having atleast one substituent selected from the group consisting of methyl,ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl, ethoxycarbonyl, amino,methylamino, ethylamino, dimethylamino, diethylamino, formamido andacetamido groups and fluorine, chlorine and bromine atoms; furyl groups;methyl-substituted furyl groups thienyl groups; and methyl-substitutedthienyl groups; a diphenylamino group; or a substituted diphenylaminogroup having at least one substituent selected from the group consistingof methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl,ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino,diethylamino, formamido and acetamido groups and fluorine, chlorine andbromine atoms; andR³ represents: a carboxy group; an alkoxycarbonylgroup having from 2 to 5 carbon atoms; a benzyloxycarbonyl group; analkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from 1 to5 carbon atoms and the alkoxy part has 1 or 2 carbon atoms; acycloalkanecarbonyloxyalkoxycarbonyl group in which the cycloalkane parthas from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms; a methoxycarbonyl or ethoxycarbonyl group which is substituted byan alkoxycarbonyloxy group having from 2 to 5 carbon atoms; acycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloalkylpart has from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms; a (5-phenyl-, 5-methyl- or5-ethyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group; aphthalidyloxycarbonyl group; or a group of formula --CONHSO₂ R⁴, whereinR⁴ represents a methyl group or an ethyl group.
 10. The compound ofclaim 1, wherein R¹ and R² are independently selected from the groupconsisting of benzyl groups and substituted benzyl groups having on thearomatic ring at least one substituent selected from the groupconsisting of methyl, methoxy, hydroxy and acetamido groups and fluorineand chlorine atoms.
 11. The compound of claim 1, wherein R¹ represents ahydrogen atom, and R² represents:a substituted alkyl group having from 1to 4 carbon atoms and having 1 or 2 substituents selected from the groupconsisting of:phenyl groups; substituted phenyl groups having at leastone substituent selected from the group consisting of methyl, methoxy,hydroxy, dimethylamino and acetamido groups and fluorine and chlorineatoms; furyl groups and thienyl groups; a diphenylamino group; or asubstituted diphenylamino group having at least one substituent selectedfrom the group consisting of methyl, methoxy, hydroxy, dimethylamino andacetamido and fluorine and chlorine atoms.
 12. The compound of claim 1,wherein R³ represents a carboxy group, a methoxycarbonyl group, anethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group, anethoxycarbonyloxymethoxycarbonyl group, a1-(ethoxycarbonyloxy)ethoxycarbonyl group, anisopropoxycarbonyloxymethoxycarbonyl group, a1-(isopropoxycarbonyloxy)ethoxycarbonyl group, a(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group, aphthalidyloxycarbonyl group or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents a methyl group.
 13. The compound of claim 1, wherein:R¹and R² are independently selected from the group consisting of benzylgroups and substituted benzyl groups having on the aromatic ring atleast one substituent selected from the group consisting of methyl,methoxy, hydroxy and acetamido groups and fluorine and chlorine atoms;and R³ represents a carboxy group, a methoxycarbonyl group, anethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group, anethoxycarbonyloxymethoxycarbonyl group, a 1-(ethoxycarbonyloxy)ethoxycarbonyl group, an isopropoxycarbonyloxymethoxycarbonyl group, a1-(isopropoxycarbonyloxy)ethoxycarbonyl group, a(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group, aphthalidyloxycarbonyl group or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents a methyl group.
 14. The compound of claim 1, wherein:R¹represents a hydrogen atom; R² represents: a substituted alkyl grouphaving from 1 to 4 carbon atoms and having 1 or 2 substituents selectedfrom the group consisting of:phenyl groups; substituted phenyl groupshaving at least one substituent selected from the group consisting ofmethyl, methoxy, hydroxy, dimethylamino and acetamido groups andfluorine and chlorine atoms; furyl groups and thienyl groups; adiphenylamino group; or a substituted diphenylamino group having atleast one substituent selected from the group consisting of methyl,methoxy, hydroxy, dimethylamino and acetamido and fluorine and chlorineatoms; andR³ represents a carboxy group, a methoxycarbonyl group, anethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group, anethoxycarbonyloxymethoxycarbonyl group, a 1-(ethoxycarbonyloxy)ethoxycarbonyl group, an isopropoxycarbonyloxymethoxycarbonyl group, a1-(isopropoxycarbonyloxy)ethoxycarbonyl group, a(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group, aphthalidyloxycarbonyl group or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents a methyl group.
 15. The compound of claim 1, wherein R¹represents a hydrogen atom, and R² represents an alkyl group having from1 to 3 carbon atoms and substituted with 1 or 2 substituents selectedfrom the group consisting of:substituted phenyl groups having at leastone substituent selected from the group consisting of methyl, methoxyand hydroxy groups and fluorine and chlorine atoms; furyl groups andthienyl groups.
 16. The compound of claim 1, wherein R³ represents acarboxy group, a methoxycarbonyl group or an ethoxycarbonyl group. 17.The compound of claim 1, wherein:R¹ represents a hydrogen atom; R²represents an alkyl group having from 1 to 3 carbon atoms andsubstituted with 1 or 2 substituents selected from the group consistingof: phenyl groups; substituted phenyl groups having at least onesubstituent selected from the group consisting of methyl, methoxy andhydroxy groups and fluorine and chlorine atoms; furyl groups and thienylgroups; and R³ represents a carboxy group, a methoxycarbonyl group or anethoxycarbonyl group.
 18. The compound of claim 1, wherein R² representsa 2-hydroxyisopropyl group or a 1-carboxyethyl group having at least onesubstituent selected from the group consisting of aryl groups as definedabove and aromatic heterocyclic groups as defined in claim
 1. 19. Thecompound of claim 1, selected from the group consisting of17-[N-(1,2-diphenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylic acidand pharmaceutically acceptable salts and esters thereof.
 20. Thecompound of claim 1, selected from the group consisting of17-[N-(diphenylmethyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid andpharmaceutically acceptable salts and esters thereof.
 21. The compoundof claim 1, selected from the group consisting of17-[N-(4,4'-dimethoxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 22. Thecompound of claim 1, selected from the group consisting of17-[N-(1-methyl-1-phenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 23. Thecompound of claim 1, selected from the group consisting of17-{N-[1-methyl-1-(2-thienyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 24. Thecompound of claim 1, selected from the group consisting of17-{N-[1-(4-fluorophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 25. Thecompound of claim 1, selected from the group consisting of17β-[N-(4-hydroxybenzhydryl)carbamoyl] androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 26. Thecompound of claim 1, selected from the group consisting of17-{N-[1-(3,5-dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 27. Thecompound of claim 1, selected from the group consisting of17-[N-(diphenylamino)carbamoyl]androsta-3,5-diene-3-carboxylic acid andpharmaceutically acceptable salts and esters thereof.
 28. The compoundof claim 1, selected from the group consisting of17-{N-[1-(3-methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 29. Thecompound of claim 1, selected from the group consisting of17-{N-[1-(2-methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 30. Thecompound of claim 1, selected from the group consisting of17-[N-(α,α-dimethylfurfuryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 31. Thecompound of claim 1, selected from the group consisting of17-{N-[1-(4-N,N-dimethylaminophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 32. Thecompound of claim 1, selected from the group consisting of17-{N-[1-(3,4-dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 33. Thecompound of claim 1, selected from the group consisting of17-{N-[1-(4-ethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 34. Thecompound of claim 1, selected from the group consisting of17-{N-[1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 35. Apharmaceutical composition for the treatment or prophylaxis of disordersarising from high levels of 5α-reductase, which composition comprises aneffective amount of an active compound in admixture with apharmaceutically acceptable carrier or diluent, wherein said activecompound is selected from the group consisting of compounds of formula(I) and pharmaceutically acceptable salts and esters thereof, as claimedin claim
 1. 36. The composition of claim 35, wherein:R¹ represents: ahydrogen atom; an isopropyl group; a benzyl group; a substituted benzylgroup having on the aromatic ring at least one substituent selected fromthe group consisting of methyl, ethyl, methoxy, ethoxy, hydroxy,ethoxycarbonyl, methoxycarbonyl, amino, methylamino, ethylamino,dimethylamino, diethylamino, formamido and acetamido groups andfluorine, chlorine and bromine atoms; or a thienylmethyl group;R²represents: a substituted alkyl group having from 1 to 4 carbon atomsand having 1 or 2 substituents selected from the group consistingof:phenyl groups; substituted phenyl groups having at least onesubstituent selected from the group consisting of methyl, ethyl,methoxy, ethoxy, hydroxy, methoxycarbonyl, ethoxycarbonyl, amino,methylamino, ethylamino, dimethylamino, diethylamino, formamido andacetamido groups and fluorine, chlorine and bromine atoms; furyl groups;methyl-substituted furyl groups thienyl groups; and methyl-substitutedthienyl groups; a diphenylamino group; or a substituted diphenylaminogroup having at least one substituent selected from the group consistingof methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl,ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino,diethylamino, formamido and acetamido groups and fluorine, chlorine andbromine atoms; andR³ represents: a carboxy group; an alkoxycarbonylgroup having from 2 to 5 carbon atoms; a benzyloxycarbonyl group; analkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from 1 to5 carbon atoms and the alkoxy part has 1 or 2 carbon atoms; acycloalkanecarbonyloxyalkoxycarbonyl group in which the cycloalkane parthas from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms; a methoxycarbonyl or ethoxycarbonyl group which is substituted byan alkoxycarbonyloxy group having from 2 to 5 carbon atoms; acycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloalkylpart has from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbonatoms; a (5-phenyl-, 5-methyl- orB-ethyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group; aphthalidyloxycarbonyl group; or a group of formula --CONHSO₂ R₄ whereinR⁴ represents a methyl group or an ethyl group.
 37. The composition ofclaim 35, wherein:R¹ and R² are independently selected from the groupconsisting of benzyl groups and substituted benzyl groups having on thearomatic ring at least one substituent selected from the groupconsisting of methyl, methoxy, hydroxy and acetamido groups and fluorineand chlorine atoms; and R³ represents a carboxy group, a methoxycarbonylgroup, an ethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group, anethoxycarbonyloxymethoxycarbonyl group, a1-(ethoxycarbonyloxy)ethoxycarbonyl group, anisopropoxycarbonyloxymethoxycarbonyl group, a 1-(isopropoxycarbonyloxy)ethoxycarbonyl group, a(5-methyl-2-oxo-l,3-dioxolen-4-yl)methoxycarbonyl group, aphthalidyloxycarbonyl group or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents a methyl group.
 38. The composition of claim 35,wherein:R¹ represents a hydrogen atom; R² represents: a substitutedalkyl group having from 1 to 4 carbon atoms and having 1 or 2substituents selected from the group consisting of:phenyl groups;substituted phenyl groups having at least one substituent selected fromthe group consisting of methyl, methoxy, hydroxy, dimethylamino andacetamido groups and fluorine and chlorine atoms; furyl groups andthienyl groups; a diphenylamino group; or a substituted diphenylaminogroup having at least one substituent selected from the group consistingof methyl, methoxy, hydroxy, dimethylamino and acetamido and fluorineand chlorine atoms; andR³ represents a carboxy group, a methoxycarbonylgroup, an ethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group, anethoxycarbonyloxymethoxycarbonyl group, a1-(ethoxycarbonyloxy)ethoxycarbonyl group, anisopropoxycarbonyloxymethoxycarbonyl group, a 1-(isopropoxycarbonyloxy)ethoxycarbonyl group, a(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl group, aphthalidyloxycarbonyl group or a group of formula --CONHSO₂ R⁴ whereinR⁴ represents a methyl group.
 39. The composition of claim 35,wherein:R¹ represents a hydrogen atom; R² represents an alkyl grouphaving from 1 to 3 carbon atoms and substituted with 1 or 2 substituentsselected from the group consisting of: phenyl groups; substituted phenylgroups having at least one substituent selected from the groupconsisting of methyl, methoxy and hydroxy groups and fluorine andchlorine atoms; furyl groups and thienyl groups; andR³ represents acarboxy group, a methoxycarbonyl group or an ethoxycarbonyl group. 40.The composition of claim 35, wherein said active compound is selectedfrom the group consistingof:17-[N-(1,2-Diphenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid; 17-[N-(Diphenylmethyl)carbamoyl]androsta -3,5-diene -3-carboxylicacid;17-[N-(4,4'-Dimethoxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid;17-[N-(1-Methyl-1-phenylethyl)carbamoyl]androsta-3,5-diene-3-carboxylicacid;17-{N-[1-Methyl-1-(2-thienyl)ethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;17-{N-[1-(4-Fluorophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid; 17β-[-N-(4-Hydroxybenzhydryl)carbamoyl]androsta-3,5-diene-3-carboxylic acid;17-{N-[1-(3,5-Dimethoxyphenyl)-1-methylethyl]carbamoyl}-androsta-3,5-diene-3-carboxylicacid; 17-[N-(Diphenylamino)carbamoyl]androsta-3,5-diene-3-carboxylicacid;17-{N-[1-(3-Methoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;17-{N-[1-(2-Methoxyphenyl)-1-methylethyl]carbamoyl}-androsta-3,5-diene-3-carboxylicacid;17-[N-(α,α-Dimethylfurfuryl)carbamoyl]androsta-3,5-diene-3-carboxylicacid;17-{N-[1-(4-N,N-Dimethylaminophenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;17-{N-[1-(3,4-Dimethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid;17-{N-[1-(4-Ethoxyphenyl)-1-methylethyl]carbamoyl}androsta-3,5-diene-3-carboxylicacid; and17-{N-[1-Methyl-1-(3,4,5-trimethoxyphenyl)ethyl]-carbamoyl}androsta-3,5-diene-3-carboxylicacid;and pharmaceutically acceptable salts and esters thereof.